Purinone compounds as kinase inhibitors

ABSTRACT

Disclosed herein are compounds that form covalent bonds with Bruton&#39;s tyrosine kinase (Btk). Also described are irreversible inhibitors of Btk. In addition, reversible inhibitors of Btk are also described. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

CROSS-REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.13/460,524, filed Apr. 30, 2012, and claims the benefit of U.S.provisional application Ser. No. 61/637,765, filed Apr. 24, 2012, andU.S. provisional application Ser. No. 61/593,146, filed Jan. 31, 2012;all of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds and compositions to inhibit theactivity of tyrosine kinases.

BACKGROUND OF THE INVENTION

Bruton's tyrosine kinase (Btk), a member of the Tec family ofnon-receptor tyrosine kinases, is a key signaling enzyme expressed inall hematopoietic cells types except T lymphocytes and natural killercells. Btk plays an essential role in the B-cell signaling pathwaylinking cell surface B-cell receptor (BCR) stimulation to downstreamintracellular responses. Btk is a key regulator of B-cell development,activation, signaling, and survival (Kurosaki, Curr Op Imm, 2000,276-281; Schaeffer and Schwartzberg, Curr Op Imm 2000, 282-288). Inaddition, Btk plays a role in a number of other hematopoetic cellsignaling pathways, e.g., Toll like receptor (TLR) and cytokinereceptor-mediated TNF-α production in macrophages, IgE receptor(FcepsilonRI) signaling in Mast cells, inhibition of Fas/APO-1 apoptoticsignaling in B-lineage lymphoid cells, and collagen-stimulated plateletaggregation. See, e.g., C. A. Jeffries, et al., (2003), Journal ofBiological Chemistry 278:26258-26264; N. J. Horwood, et al., (2003), TheJournal of Experimental Medicine 197:1603-1611; Iwaki et al. (2005),Journal of Biological Chemistry 280(48):40261-40270; Vassilev et al.(1999), Journal of Biological Chemistry 274(3):1646-1656, and Quek etal. (1998), Current Biology 8(20):1137-1140.

SUMMARY OF THE INVENTION

Described herein are inhibitors of Bruton's tyrosine kinase (Btk). Alsodescribed herein are irreversible inhibitors of Btk. Also describedherein are reversible inhibitors of Btk. Further described areirreversible inhibitors of Btk that form a covalent bond with a cysteineresidue on Btk. Further described herein are irreversible inhibitors ofother tyrosine kinases, wherein the other tyrosine kinases sharehomology with Btk by having a cysteine residue (including a Cys 481residue) that can form a covalent bond with the irreversible inhibitor.

Also described herein are methods for synthesizing such reversible orirreversible inhibitors, methods for using such reversible orirreversible inhibitors in the treatment of diseases (including diseaseswherein irreversible inhibition of Btk provides therapeutic benefit to apatient having the disease). Further described are pharmaceuticalformulations that include a reversible or irreversible inhibitor of Btk.

In one aspect, provided herein is a compound of Formula (I) having thestructure:

wherein:

-   -   L_(a) is a bond, —CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂,        —CH₂S—, —N(R₂₁)—, —N(R₂₁)C(O)—, —C(O)N(R₂₁)—,        —N(R₂₁)C(O)N(R₂₁)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R₂₁)S(O)₂—, or        —S(O)₂N(R₂₁)—;    -   Ar is a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl;    -   R₃ is optionally substituted C₃-C₆ alkyl, substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heteroaryl, —(C═O)C₁-C₆ alkyl, —(C═O)OR₄, —(C═O)NR₄R₄,        —(C═O)SR₄, -G-X, or

-   -   G is optionally substituted heterocycloalkyl, optionally        substituted aryl, or optionally substituted heteroaryl;    -   X is optionally substituted cycloalkyl; optionally substituted        heterocycloalkyl; optionally substituted aryl, optionally        substituted heteroaryl, —OR₄, —SR₄, or —NR₄R₄;    -   each R₄ is each independently H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl,        C₃-C₆ cycloalkyl, or C₂-C₆ heterocycloalkyl;    -   Y is an optionally substituted group selected from among alkyl,        heteroalkyl, cycloalkyl, aryl, and heteroaryl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   p is 0-2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond; L and J are each independently a bond,        substituted or unsubstituted C₁-C₆ alkylene, substituted or        unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted        C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, halogen, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (I) wherein L_(a) is —O— or—OCH₂—. In a further embodiment is a compound of Formula (I) whereinL_(a) is —O—. In yet a further embodiment L_(a) is —OCH₂—. In anotherembodiment is a compound of Formula (I) wherein Ar is phenyl.

In another embodiment is a compound of Formula (I) wherein R₃ isoptionally substituted C₃-C₆alkyl. In another embodiment is a compoundof Formula (I) wherein R₃ is substituted cycloalkyl. In a furtherembodiment is a compound of Formula (I) wherein R₃ is optionallysubstituted aryl. In a further embodiment is a compound of Formula (I)wherein R₃ is optionally substituted heteroaryl. In another embodimentis a compound of Formula (I) wherein R₃ is G-X. In a further embodimentis a compound of Formula (I) wherein G is selected from pyrrolidinyl,tetrahydrofuranyl, piperidinyl, piperizinyl, and morpholinyl. In afurther embodiment is a compound of Formula (I) wherein X is optionallysubstituted heterocycloalkyl. In yet a further embodiment is a compoundof Formula (I) wherein X is pyrrolidinyl, tetrahydrofuranyl,piperidinyl, piperizinyl, and morpholinyl. In another embodiment is acompound of Formula (I) wherein X is —OR₄, —SR₄, or —NR₄R₄.

In another embodiment is a compound of Formula (I) wherein R₃ is

In some embodiments, Z is C(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂.

In another embodiment is a compound of Formula (I) wherein R₆, R₇, andR₈ are H. In another embodiment is a compound of Formula (I) wherein R₆is H; R₈ is —CN; and R₇ is L-J-W. In another embodiment is a compound ofFormula (I) wherein R₆ is H; R₈ is —CN; and R₇ is C₃-C₆ cycloalkyl,C₆-C₁₂ aryl, or C₃-C₁₂ heteroaryl. In another embodiment is a compoundof Formula (I) wherein R₆ is H; R₈ is —CN; and R₇ is cyclopropyl orphenyl. In another embodiment is a compound of Formula (I) wherein R₇and R₈ are H; and R₆ is L-J-W. In a further embodiment is a compound ofFormula (I) wherein R₆ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (I) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In another embodiment isa compound of Formula (I) wherein R₆ and R₈ are H; and R₇ is L-J-W. Inanother embodiment is a compound of Formula (I) wherein R₇ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (I) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₆ and R₈ areH; R₇ is L-J-W;

-   -   L is a bond, substituted or unsubstituted C₁-C₆ alkylene, or        substituted or unsubstituted C₃-C₆ cycloalkylene; and J is a        bond, substituted or unsubstituted C₁-C₆ alkylene, substituted        or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.        In a further embodiment is a compound of Formula (I) wherein L        is —CH₂—. In a further embodiment is a compound of Formula (I)        wherein J is substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.        In yet a further embodiment is a compound of Formula (I) wherein        J is substituted or unsubstituted C₁-C₆ alkylene, cyclopropyl,        pyrrolidinyl, piperidinyl, piperizinyl, morpholinyl, imidazolyl,        pyridinyl, or phenyl. In a further embodiment is a compound of        Formula (I) wherein L is a bond. In a further embodiment is a        compound of Formula (I) wherein J is substituted or        unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted        C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.        In yet a further embodiment is a compound of Formula (I) wherein        J is —CH₂—; and W is NR₂₅R₂₆. In another embodiment is a        compound of Formula (I) wherein L is a bond; J is —CH₂—; and W        is NR₂₅R₂₆. In a further embodiment is a compound of Formula (I)        wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, or        substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is        substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or        substituted or unsubstituted C₃-C₁₂ heteroaryl. In some        embodiments is a compound of Formula (I) wherein R₂₅ and R₂₆ are        —CH₃. In some embodiments is a compound of Formula (I) wherein        R₂₅ and R₂₆ are cyclopropyl. In some embodiments is a compound        of Formula (I) wherein R₂₅ is —CH₃ and R₂₆ is cyclopropyl.

In another embodiment is a compound of Formula (I) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In another embodiment is acompound of Formula (I) wherein R₆ is H, substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (I) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In yet anotherembodiment is a compound of Formula (I) wherein R₆ is substituted orunsubstituted C₁-C₆alkyl, or C₁-C₈alkylaminoalkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein Y is phenyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein Y is cycloalkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein Z is C(═O).

In one aspect, provided herein is a compound of Formula (II) having thestructure:

wherein:

-   -   L_(a) is a bond, —CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂,        —CH₂S—, —N(R₂₁)—, —N(R₂₁)C(O)—, —C(O)N(R₂₁)—,        —N(R₂₁)C(O)N(R₂₁)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R₂₁)S(O)₂—, or        —S(O)₂N(R₂₁)—;    -   Ar is a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl;    -   R₃ is

-   -   Y is an optionally substituted heterocycloalkyl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   p is 0-2;    -   R₆ and R₈ are independently H or L-J, and R₇ is T-W; or    -   R₆ and R₇ are independently H or L-J, and R₈ is T-W; or    -   R₇ and R₈ are independently H or L-J, and R₆ is T-W; or    -   R₇ and R₈ taken together form a bond, and R₆ is T-W;    -   L is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   J is substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl,        NR₂₇R₂₈, or substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   T is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene, or        —S—;    -   W is NR₂₅R₂₆, —CN, substituted or unsubstituted C₃-C₆cycloalkyl,        or substituted or unsubstituted C-linked C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₆-C₁₂ aryl, or substituted or        unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or        substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₂-C₇ heterocycloalkyl, substituted or        unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl;    -   R₂₇ and R₂₈ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₇ and R₂₈ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (II) wherein L_(a) is —O—. Inanother embodiment is a compound of Formula (II) wherein Ar is phenyl.

In another embodiment is a compound of Formula (II) wherein Z is C(═O),NHC(═O), N(CH₃)C(═O), or S(═O)₂.

In another embodiment is a compound of Formula (II) wherein R₆ is H; R₈is —CN; and R₇ is L-J. In another embodiment is a compound of Formula(II) wherein R₆ is H; R₈ is —CN; and R₇ is C₃-C₆ cycloalkyl, C₆-C₁₂aryl, or C₃-C₁₂ heteroaryl. In another embodiment is a compound ofFormula (II) wherein R₆ is H; R₈ is —CN; and R₇ is cyclopropyl orphenyl.

In another embodiment is a compound of Formula (II) wherein R₇ and R₈are H; and R₆ is T-W. In another embodiment is a compound of Formula(II) wherein R₆ and R₈ are H; and R₇ is T-W. In yet another embodimentis a compound of Formula (II) wherein R₇ and R₈ taken together form abond; and R₆ is T-W. In a further embodiment is a compound of Formula(II) wherein T is a bond, substituted or unsubstituted C₁-C₆ alkylene,or substituted or unsubstituted C₃-C₆ cycloalkylene. In yet a furtherembodiment is a compound of Formula (II) wherein T is —CH₂—. In afurther embodiment is a compound of Formula (II) wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, or substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In a further embodiment is a compound of Formula (II)wherein W is cyclopropyl, imidazolyl, pyridinyl, or phenyl. In anotherembodiment is a compound of Formula (II) wherein W is NR₂₅R₂₆. Inanother embodiment is a compound of Formula (II) wherein T is —CH₂—; andW is NR₂₅R₂₆. In a further embodiment is a compound of Formula (II)wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In another embodiment is a compound ofFormula (II) wherein R₂₅ and R₂₆ are substituted or unsubstitutedC₃-C₆cycloalkyl. In some embodiments is a compound of Formula (II)wherein R₂₅ and R₂₆ are cyclopropyl. In another embodiment is a compoundof Formula (II) wherein R₂₅ is substituted or unsubstituted C₁-C₆ alkyl;and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In anotherembodiment is a compound of Formula (II) wherein R₂₅ is —CH₃; and R₂₆ issubstituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments is acompound of Formula (II) wherein R₂₅ is —CH₃; and R₂₆ is cyclopropyl. Ina further embodiment of the aforementioned embodiments is a compound ofFormula (II) wherein Y is pyrrolidinyl or piperidinyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein Z is C(═O).

In another aspect, provided herein is a compound of Formula (III) havingthe structure:

wherein:

-   -   A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   R₂₀ is H, halogen, —CN, —CF₃, —NO₂, —OH, substituted or        unsubstituted C₁-C₆alkyl, —N(R₂₁)C(═O)R₂₃, —C(═O)N(R₂₁)(R₂₂),        —O—(C₁-C₆alkyl), —O-alkylene-OR₂₁, —CO₂H, —O-alkylene-CO₂H,        —O-alkylene-C(═O)N(R₂₁)(R₂₂), or —N(R₂₁)C(═O)N(R₂₁)(R₂₂);    -   each R₂₁ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₂ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₃ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   p is 0-2;    -   n is 0-4;    -   R₃ is optionally substituted alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —(C═O)C₁-C₆        alkyl, —(C═O)OR₄, —(C═O)NR₄R₄, —(C═O)SR₄, -G-X, or

-   -   G is optionally substituted heterocycloalkyl, optionally        substituted aryl, or optionally substituted heteroaryl;    -   X is optionally substituted cycloalkyl; optionally substituted        heterocycloalkyl; optionally substituted aryl, optionally        substituted heteroaryl, —OR₄, —SR₄, or —NR₄R₄;    -   each R₄ is each independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,        C₃-C₆ cycloalkyl, or C₂-C₆ heterocycloalkyl;    -   Y is an optionally substituted group selected from among alkyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring; or a        pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (III) wherein A is aryl. Inanother embodiment is a compound of Formula (III) wherein A is phenyl.

In another embodiment is a compound of Formula (III) wherein R₂₀ is H,halogen, —CN, —CF₃, or substituted or unsubstituted C₁-C₆alkyl. In someembodiments is a compound of Formula (III) wherein R₂₀ is H. In someembodiments is a compound of Formula (III) wherein R₂₀ is —CN. In someembodiments is a compound of Formula (III) wherein R₂₀ is —CF₃. In someembodiments is a compound of Formula (III) wherein R₂₀ is halogen. Insome embodiments is a compound of Formula (III) wherein R₂₀ is F or Cl.In some embodiments is a compound of Formula (III) wherein R₂₀ issubstituted or unsubstituted C₁-C₆alkyl.

In a further embodiment is a compound of Formula (III) wherein R₃ isoptionally substituted alkyl. In another embodiment is a compound ofFormula (III) wherein R₃ is optionally substituted cycloalkyl. Inanother embodiment is a compound of Formula (III) wherein R₃ isoptionally substituted heterocycloalkyl.

In another embodiment is a compound of Formula (III) wherein R₃ is

In further embodiments, Z is C(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂.

In another embodiment is a compound of Formula (III) wherein R₆, R₇, andR₈ are H. In another embodiment is a compound of Formula (III) whereinR₆ is H; R₈ is —CN; and R₇ is L-J-W. In another embodiment is a compoundof Formula (III) wherein R₆ is H; R₈ is —CN; and R₇ is C₃-C₆ cycloalkyl,C₆-C₁₂ aryl, or C₃-C₁₂ heteroaryl. In another embodiment is a compoundof Formula (III) wherein R₆ is H; R₈ is —CN; and R₇ is cyclopropyl orphenyl. In another embodiment is a compound of Formula (III) wherein R₇and R₈ are H; and R₆ is L-J-W. In a further embodiment is a compound ofFormula (III) wherein R₆ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (III) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In another embodiment isa compound of Formula (III) wherein R₆ and R₈ are H; and R₇ is L-J-W. Inanother embodiment is a compound of Formula (III) wherein R₇ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In a further embodiment is a compoundof Formula (III) wherein R₇ is substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In a further embodimentis a compound of Formula (III) wherein R₇ is —CH₂N(CH₃)₂. In yet afurther embodiment is a compound of Formula (III) wherein R₇ is

In another embodiment is a compound of Formula (III) wherein R₆ and R₈are H; R₇ is L-J-W. In a further embodiment, L is a bond, substituted orunsubstituted C₁-C₆ alkylene, or substituted or unsubstituted C₃-C₆cycloalkylene; and J is a bond, substituted or unsubstituted C₁-C₆alkylene, substituted or unsubstituted C₃-C₆ cycloalkylene, substitutedor unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstitutedC₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene,or substituted or unsubstituted C₃-C₁₂ heteroarylene. In a furtherembodiment is a compound of Formula (III) wherein L is —CH₂—. In afurther embodiment is a compound of Formula (III) wherein J issubstituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In yet a further embodiment is acompound of Formula (III) wherein J is substituted or unsubstitutedC₁-C₆ alkylene, cyclopropyl, pyrrolidinyl, piperidinyl, piperizinyl,morpholinyl, imidazolyl, pyridinyl, or phenyl. In a further embodimentis a compound of Formula (III) wherein L is a bond. In a furtherembodiment is a compound of Formula (III) wherein J is substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In yet a further embodiment is acompound of Formula (III) wherein J is —CH₂—; and W is NR₂₅R₂₆. Inanother embodiment is a compound of Formula (III) wherein L is a bond; Jis —CH₂—; and W is NR₂₅R₂₆. In a further embodiment is a compound ofFormula (III) wherein R₂₅ is H, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ issubstituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In some embodiments is a compound of Formula (III) whereinR₂₅ and R₂₆ are —CH₃. In some embodiments is a compound of Formula (III)wherein R₂₅ and R₂₆ are cyclopropyl. In some embodiments is a compoundof Formula (III) wherein R₂₅ is —CH₃ and R₂₆ is cyclopropyl.

In another embodiment is a compound of Formula (III) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In a further embodiment isa compound of Formula (III) wherein R₆ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (III) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein Y is aryl or heterocycloalkyl. In a furtherembodiment is a compound of Formula (III) wherein Y is phenyl,pyrrolidinyl, or piperidinyl. In yet a further embodiment is a compoundof Formula (III) wherein Y is phenyl, pyrrolidinyl, or piperidinyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein Y is selected from

wherein m is 0 to 3. In a further embodiment of the aforementionedembodiments is a compound of Formula (III) wherein Z is C(═O).

In a further embodiment of the aforementioned embodiments wherein A isphenyl is a compound of Formula (III) wherein R₂₀ is attached to thephenyl ring at the para position relative to the purinone ring. Inanother embodiment of the aforementioned embodiments wherein A is phenylis a compound of Formula (III) wherein R₂₀ is attached to the phenylring at the meta position relative to the purinone ring. In yet anotherembodiment of the aforementioned embodiments wherein A is phenyl is acompound of Formula (III) wherein R₂₀ is attached to the phenyl ring atthe ortho position relative to the purinone ring.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb),or (IIIc) wherein p is 0. In a further embodiment of the aforementionedembodiments is a compound of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc) wherein n is 0.

In another aspect is a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) and apharmaceutically acceptable excipient. In a further embodiment is apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula (I). In another embodiment is a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula (II). In another embodiment is a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of Formula(III). In one embodiment, the pharmaceutical composition comprising thecompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is formulated for a route of administration selectedfrom oral administration, parenteral administration, buccaladministration, nasal administration, topical administration, or rectaladministration. In another aspect is a method for treating an autoimmunedisease or condition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In oneembodiment the autoimmune disease is selected from rheumatoid arthritisor lupus. In a further aspect is a method for treating a heteroimmunedisease or condition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In yetanother embodiment is a method for treating a cancer comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc). In one embodiment the cancer is a B-cellproliferative disorder.

In another embodiment the B-cell proliferative disorder is diffuse largeB cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia.

In yet a further aspect is a method for treating mastocytosis comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc).

In another aspect is a method for treating osteoporosis or boneresorption disorders comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc).

In a further aspect is a method for treating an inflammatory disease orcondition comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc).

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In a further aspect are provided pharmaceutical compositions, whichinclude a therapeutically effective amount of at least one of any of thecompounds herein, or a pharmaceutically acceptable salt,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate. In certain embodiments,compositions provided herein further include a pharmaceuticallyacceptable diluent, excipient and/or binder.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically effectivederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases,disorders or conditions that are modulated or otherwise affected bytyrosine kinase activity, or in which tyrosine kinase activity isimplicated, are provided. The effective amounts and concentrations areeffective for ameliorating any of the symptoms of any of the diseases,disorders or conditions disclosed herein.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

In one aspect, provided herein are methods for treating a patient byadministering a compound provided herein. In some embodiments, providedherein is a method of inhibiting the activity of tyrosine kinase(s),such as Btk, or of treating a disease, disorder, or condition, whichwould benefit from inhibition of tyrosine kinase(s), such as Btk, in apatient, which includes administering to the patient a therapeuticallyeffective amount of at least one of any of the compounds herein, orpharmaceutically acceptable salt, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate.

In another aspect, provided herein is the use of a compound disclosedherein for inhibiting Bruton's tyrosine kinase (Btk) activity or for thetreatment of a disease, disorder, or condition, which would benefit frominhibition of Bruton's tyrosine kinase (Btk) activity.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In other embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of tyrosine kinaseactivity. In some other embodiments, compounds provided herein are usedfor the formulation of a medicament for the inhibition of Bruton'styrosine kinase (Btk) activity.

Articles of manufacture including packaging material, a compound orcomposition or pharmaceutically acceptable derivative thereof providedherein, which is effective for inhibiting the activity of tyrosinekinase(s), such as Btk, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable salt, pharmaceutically active metabolite, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate thereof, isused for inhibiting the activity of tyrosine kinase(s), such as Btk, areprovided.

In another aspect are inhibited tyrosine kinases comprising a Bruton'styrosine kinase covalently bound to an inhibitor having the structure:

wherein

indicates the point of attachment between the inhibitor and the tyrosinekinase. In a further embodiment, the inhibitor is covalently bound to acysteine residue on the tyrosine kinase.

In another aspect are inhibited tyrosine kinases comprising a Bruton'styrosine kinase covalently bound to an inhibitor having the structure:

wherein

indicates the point of attachment between the inhibitor and the tyrosinekinase. In a further embodiment, the inhibitor is covalently bound to acysteine residue on the tyrosine kinase.

In a further aspect, provided herein is a method for inhibiting Bruton'styrosine kinase in a subject in need thereof by administering to thesubject thereof a composition containing a therapeutically effectiveamount of at least one compound having the structure of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). Insome embodiments, the subject in need is suffering from an autoimmunedisease, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia.

In other embodiments, the subject in need is suffering from aheteroimmune condition or disease, e.g., graft versus host disease,transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In certain embodiments, the subject in need is suffering from aninflammatory disease, e.g., asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In further embodiments, the subject in need is suffering from a cancer.In one embodiment, the cancer is a B-cell proliferative disorder, e.g.,diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds. In one embodiment, the anti-cancer agent is an inhibitor ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002.

In further embodiments, the subject in need is suffering from athromboembolic disorder, e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, or deep venous thrombosis.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In one embodiment, theautoimmune disease is arthritis. In another embodiment, the autoimmunedisease is lupus. In some embodiments, the autoimmune disease isinflammatory bowel disease (including Crohn's disease and ulcerativecolitis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis,Still's disease, juvenile arthritis, lupus, diabetes, myasthenia gravis,Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease Sjögren'ssyndrome, multiple sclerosis, Guillain-Barré syndrome, acutedisseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonussyndrome, ankylosing spondylitisis, antiphospholipid antibody syndrome,aplastic anemia, autoimmune hepatitis, coeliac disease, Goodpasture'ssyndrome, idiopathic thrombocytopenic purpura, optic neuritis,scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu'sarteritis, temporal arteritis, warm autoimmune hemolytic anemia,Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet'sdisease, chronic fatigue, dysautonomia, endometriosis, interstitialcystitis, neuromyotonia, scleroderma, or vulvodynia.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount ofat least one compound having the structure of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In someembodiments, the heteroimmune condition or disease is graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In some embodiments, theinflammatory disease is asthma, inflammatory bowel disease (includingCrohn's disease and ulcerative colitis), appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In yet another aspect, provided herein is a method for treating a cancerby administering to a subject in need thereof a composition containing atherapeutically effective amount of at least one compound having thestructure of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc). In one embodiment, the cancer is a B-cellproliferative disorder, e.g., diffuse large B cell lymphoma, follicularlymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia,B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis. Insome embodiments, where the subject is suffering from a cancer, ananti-cancer agent is administered to the subject in addition to one ofthe above-mentioned compounds. In one embodiment, the anti-cancer agentis an inhibitor of mitogen-activated protein kinase signaling, e.g.,U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125,BAY 43-9006, wortmannin, or LY294002.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In some embodiments, thethromboembolic disorder is myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, or deep venous thrombosis.

In a further aspect, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bound with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In a further aspect, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount of acompound that forms a covalent bond with Bruton's tyrosine kinase. Inone embodiment, the compound forms a covalent bound with the activatedform of Bruton's tyrosine kinase. In further or alternative embodiments,the compound irreversibly inhibits the Bruton's tyrosine kinase to whichit is covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In a further aspect, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bound with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase. In yet another aspect, provided herein is a method fortreating a cancer by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bound with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In another aspect, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundthat forms a covalent bond with Bruton's tyrosine kinase. In oneembodiment, the compound forms a covalent bound with the activated formof Bruton's tyrosine kinase. In further or alternative embodiments, thecompound irreversibly inhibits the Bruton's tyrosine kinase to which itis covalently bound. In a further or alternative embodiment, thecompound forms a covalent bond with a cysteine residue on Bruton'styrosine kinase.

In another aspect are methods for modulating, including irreversiblyinhibiting the activity of Btk or other tyrosine kinases, wherein theother tyrosine kinases share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withat least one irreversible inhibitor described herein, in a mammalcomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In anotheraspect are methods for modulating, including reversibly or irreversiblyinhibiting, the activity of Btk in a mammal comprising administering tothe mammal at least once an effective amount of at least one compoundhaving the structure of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), or (IIIc). In another aspect are methods fortreating Btk-dependent or Btk mediated conditions or diseases,comprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc).

In another aspect are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc).

A further aspect are methods for the treatment of cancer comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). The type of cancermay include, but is not limited to, pancreatic cancer and other solid orhematological tumors.

In another aspect are methods for treating respiratory diseasescomprising administering to the mammal at least once an effective amountof at least one compound having the structure of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In a furtherembodiment of this aspect, the respiratory disease is asthma. In afurther embodiment of this aspect, the respiratory disease includes, butis not limited to, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-inducedasthma, isocapnic hyperventilation, child-onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, or seasonal asthma.

In another aspect are methods for preventing rheumatoid arthritis andosteoarthritis comprising administering to the mammal at least once aneffective amount of at least one compound having the structure ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc).

In another aspect are methods for treating inflammatory responses of theskin comprising administering to the mammal at least once an effectiveamount of at least one compound having the structure of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). Suchinflammatory responses of the skin include, by way of example,dermatitis, contact dermatitis, eczema, urticaria, rosacea, andscarring. In another aspect are methods for reducing psoriatic lesionsin the skin, joints, or other tissues or organs, comprisingadministering to the mammal an effective amount of a first compoundhaving the structure of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), or (IIIc).

In another aspect is the use of a compound of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) in the manufactureof a medicament for treating an inflammatory disease or condition in ananimal in which the activity of Btk or other tyrosine kinases, whereinthe other tyrosine kinases share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withat least one irreversible inhibitor described herein, contributes to thepathology and/or symptoms of the disease or condition. In one embodimentof this aspect, the tyrosine kinase protein is Btk. In another orfurther embodiment of this aspect, the inflammatory disease orconditions are respiratory, cardiovascular, or proliferative diseases.

In any of the aforementioned aspects are further embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) theeffective amount of the compound is systemically administered to themammal; (b) the effective amount of the compound is administered orallyto the mammal; (c) the effective amount of the compound is intravenouslyadministered to the mammal; (d) the effective amount of the compoundadministered by inhalation; (e) the effective amount of the compound isadministered by nasal administration; or (f) the effective amount of thecompound is administered by injection to the mammal; (g) the effectiveamount of the compound is administered topically (dermal) to the mammal;(h) the effective amount of the compound is administered by ophthalmicadministration; or (i) the effective amount of the compound isadministered rectally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredin a single dose; (ii) the time between multiple administrations isevery 6 hours; (iii) the compound is administered to the mammal every 8hours. In further or alternative embodiments, the method comprises adrug holiday, wherein the administration of the compound is temporarilysuspended or the dose of the compound being administered is temporarilyreduced; at the end of the drug holiday, dosing of the compound isresumed. The length of the drug holiday can vary from 2 days to 1 year.

In any of the aforementioned aspects involving the treatment ofproliferative disorders, including cancer, are further embodimentscomprising administering at least one additional agent selected from thegroup consisting of alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase inhibitors such as irinotecanor topotecan, tyrosine kinase inhibitors such as gefinitinib orimatinib, or agents to treat signs or symptoms induced by such therapyincluding allopurinol, filgrastim, pegfilgrastim,granisetron/ondansetron/palonosetron, dronabinol.

In any of the aforementioned aspects involving the prevention ortreatment of Btk-dependent or tyrosine kinase mediated diseases orconditions are further embodiments comprising identifying patients byscreening for a tyrosine kinase gene haplotype. In further oralternative embodiments the tyrosine kinase gene haplotype is a tyrosinekinase pathway gene, while in still further or alternative embodiments,the tyrosine kinase gene haplotype is a Btk haplotype.

In a further or alternative embodiments, the compounds of Formula (I) or(III) are reversible inhibitors of Bruton's tyrosine kinase (Btk), whilein still further or alternative embodiments, such reversible inhibitorsare selective for Btk. In even further or alternative embodiments, suchinhibitors have an IC₅₀ below 10 microM in enzyme assay. In oneembodiment, a Btk reversible inhibitor has an IC₅₀ of less than 1microM, and in another embodiment, less than 0.25 microM.

In further or alternative embodiments, the compounds of Formula (I) or(III) are selective reversible inhibitors for Btk over Itk. In furtheror alternative embodiments, the compounds of Formula (I), or (III) areselective reversible inhibitors for Btk over Lck. In further oralternative embodiments, the compounds of Formula (I) or (III) areselective reversible inhibitors for Btk over ABL. In further oralternative embodiments, the compounds of Formula (I) or (III) areselective reversible inhibitors for Btk over CMET. In further oralternative embodiments, the compounds of Formula (I) or (III) areselective reversible inhibitors for Btk over EGFR. In further oralternative embodiments, the compounds of Formula (I) or (III) areselective reversible inhibitors for Btk over Lyn.

In further or alternative embodiments, the reversible Btk inhibitors arealso inhibitors of EGFR.

In a further or alternative embodiment, the compound of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) areirreversible inhibitors of Bruton's tyrosine kinase (Btk), while instill further or alternative embodiments, such irreversible inhibitorsare selective for Btk. In even further or alternative embodiments, suchinhibitors have an IC₅₀ below 10 microM in enzyme assay. In oneembodiment, a Btk irreversible inhibitor has an IC₅₀ of less than 1microM, and in another embodiment, less than 0.25 microM.

In further or alternative embodiment, the compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) are selectiveirreversible inhibitors for Btk over Itk. In further or alternativeembodiment, the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), or (IIIc) are selective irreversible inhibitorsfor Btk over Lck. In further or alternative embodiment, the compound ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc) are selective irreversible inhibitors for Btk over ABL. Infurther or alternative embodiment, the compound of (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) are selectiveirreversible inhibitors for Btk over CMET. In further or alternativeembodiment, the compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), or (IIIc) are selective irreversible inhibitorsfor Btk over EGFR. In further or alternative embodiment, the compound ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc) are selective irreversible inhibitors for Btk over Lyn.

In further or alternative embodiments, the irreversible Btk inhibitorsare also inhibitors of EGFR.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin the application including, but not limited to, patents, patentapplications, articles, books, manuals, and treatises are herebyexpressly incorporated by reference in their entirety for any purpose.

CERTAIN TERMINOLOGY

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereare a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in the applicationincluding, but not limited to, patents, patent applications, articles,books, manuals, and treatises are hereby expressly incorporated byreference in their entirety for any purpose.

Definition of standard chemistry terms may be found in reference works,including Carey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.”Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwiseindicated, conventional methods of mass spectroscopy, NMR, HPLC, proteinchemistry, biochemistry, recombinant DNA techniques and pharmacology,within the skill of the art are employed. Unless specific definitionsare provided, the nomenclature employed in connection with, and thelaboratory procedures and techniques of, analytical chemistry, syntheticorganic chemistry, and medicinal and pharmaceutical chemistry describedherein are those known in the art. Standard techniques can be used forchemical syntheses, chemical analyses, pharmaceutical preparation,formulation, and delivery, and treatment of patients. Standardtechniques can be used for recombinant DNA, oligonucleotide synthesis,and tissue culture and transformation (e.g., electroporation,lipofection). Reactions and purification techniques can be performede.g., using kits of manufacturer's specifications or as commonlyaccomplished in the art or as described herein. The foregoing techniquesand procedures can be generally performed of conventional methods wellknown in the art and as described in various general and more specificreferences that are cited and discussed throughout the presentspecification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein,which will be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein byreference in their entirety for the purpose of describing anddisclosing, for example, the constructs and methodologies that aredescribed in the publications, which might be used in connection withthe methods, compositions and compounds described herein. Thepublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the inventors described herein arenot entitled to antedate such disclosure by virtue of prior invention orfor any other reason.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In other embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.

The alkyl group could also be a “lower alkyl” having 1 to 6 carbonatoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to twelve carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to four carbon atoms. Thealkenyl is attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Inother embodiments, an alkynyl has two to four carbon atoms. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))S(O)_(t)R^(a) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain is optionally substituted by oneor more of the following substituents: halo, cyano, nitro, aryl,cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, andwhere each of the above substituents is unsubstituted unless otherwiseindicated.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. Aryl groupsinclude, but are not limited to, groups such as phenyl, fluorenyl, andnaphthyl. Unless stated otherwise specifically in the specification, theterm “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted aralkenyl, optionally substitutedaralkynyl, optionally substituted carbocyclyl, optionally substitutedcarbocyclylalkyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substituted heteroaryl,optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroarylor heteroarylalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, benzyl, diphenylmethyland the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In other embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is optionally saturated,(i.e., containing single C—C bonds only) or unsaturated (i.e.,containing one or more double bonds or triple bonds.) A fully saturatedcarbocyclyl radical is also referred to as “cycloalkyl.” Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcarbocyclyl is also referred to as “cycloalkenyl.” Examples ofmonocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbomyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted byone or more substituents independently selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcarbocyclyl, optionally substituted carbocyclylalkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, —R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl,heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodosubstituents.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In other embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical is optionally substituted as defined above for analkyl group.

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three, four, five, six, seven, eight, nine, or morethan nine atoms. Heterocycloalkyl rings can be optionally substituted.In certain embodiments, non-aromatic heterocycles contain one or morecarbonyl or thiocarbonyl groups such as, for example, oxo- andthio-containing groups. Examples of heterocycloalkyls include, but arenot limited to, lactams, lactones, cyclic imides, cyclic thioimides,cyclic carbamates, tetrahydrothiopyran, 4H-pyran, tetrahydropyran,piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane,piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane,isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone,thiazoline, thiazolidine, and 1,3-oxathiolane. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Examples of heteroaryls include, but are not limited to,azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl,benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted carbocyclyl,optionally substituted carbocyclylalkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl, optionally substituted heteroarylalkyl,—R^(b)—OR^(a), —R^(b)—SR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Sulfanyl” refers to the —S— radical.

“Sulfinyl” refers to the —S(═O)— radical.

“Sulfonyl” refers to the —S(═O)₂— radical.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Imino” refers to the ═NH radical.

“Thioxo” refers to the ═S radical.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

“Cycloalkylalkyl” means an alkyl radical, as defined herein, substitutedwith a cycloalkyl group. Non-limiting cycloalkylalkyl groups includecyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, and the like.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms is aheteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus orcombinations thereof. The heteroatom(s) may be placed at any interiorposition of the heteroalkyl group or at the position at which theheteroalkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “alkylthioalkyl” group refers to an alkyl group substituted with a—S-alkyl group.

As used herein, the term “O-carboxy” or “acyloxy” refers to a group offormula RC(═O)O—.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

“Acyl” refers to the group —C(O)R.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

“Cyanoalkyl” means an alkyl radical, as defined herein, substituted withat least one cyano group.

As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to agroup of formula RS(═O)₂NH—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)NR₂.

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formula—OC(═S)NR₂.

As used herein, “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)NR₂.

“Aminocarbonyl” refers to a —CONH2 radical.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

An “alkenyloxy” group refers to a (alkenyl)O— group, where alkenyl is asdefined herein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached, canoptionally form a cyclic ring system.

“Alkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, as defined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are known to those of skill in the art and can readily befound in reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additionalgroup(s). By way of example only, optional substituents may be, but arenot limited to, alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic,hydroxy, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide,arylsulfoxide, alkylsulfone, arylsulfone, cyano, halo, acyl, nitro,haloalkyl, fluoroalkyl, amino, including mono- and di-substituted aminogroups, and the protected derivatives thereof. A further example ofoptional substituents may be, but are not limited to, L_(s)R_(s),wherein each L_(s) is independently selected from a bond, —O—, —C(═O)—,—S—, —S(═O)—, —S(═O)₂—, —NH—, —NHC(O)—, —C(O)NH—, S(═O)₂NH—, —NHS(═O)₂,—OC(O)NH—, —NHC(O)O—, -(substituted or unsubstituted C₁-C₆ alkyl), or-(substituted or unsubstituted C₂-C₆ alkenyl); and each R_(s) isindependently selected from H, (substituted or unsubstitutedC₁-C₄alkyl), (substituted or unsubstituted C₃-C₆cycloalkyl), heteroaryl,or heteroalkyl. The protecting groups that may form the protectivederivatives of the above substituents are known to those of skill in theart and may be found in references such as Greene and Wuts, above.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, the term “agonist” refers to a compound, the presence ofwhich results in a biological activity of a protein that is the same asthe biological activity resulting from the presence of a naturallyoccurring ligand for the protein, such as, for example, Btk.

As used herein, the term “partial agonist” refers to a compound thepresence of which results in a biological activity of a protein that isof the same type as that resulting from the presence of a naturallyoccurring ligand for the protein, but of a lower magnitude.

As used herein, the term “antagonist” refers to a compound, the presenceof which results in a decrease in the magnitude of a biological activityof a protein. In certain embodiments, the presence of an antagonistresults in complete inhibition of a biological activity of a protein,such as, for example, Btk. In certain embodiments, an antagonist is aninhibitor.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as, compounds of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), dosed that isdelivered into the general circulation of the animal or human beingstudied. The total exposure (AUC_((0-∞))) of a drug when administeredintravenously is usually defined as 100% bioavailable (F %). “Oralbioavailability” refers to the extent to which compounds disclosedherein, such as, compounds of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), are absorbed into thegeneral circulation when the pharmaceutical composition is taken orallyas compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as, compounds of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), in the plasmacomponent of blood of a subject. It is understood that the plasmaconcentration of compounds of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), may vary significantlybetween subjects, due to variability with respect to metabolism and/orpossible interactions with other therapeutic agents. In accordance withone embodiment disclosed herein, the blood plasma concentration of thecompounds of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc), may vary from subject to subject. Likewise,values such as maximum plasma concentration (C_(max)) or time to reachmaximum plasma concentration (T_(max)), or total area under the plasmaconcentration time curve (AUC_((0-∞))) may vary from subject to subject.Due to this variability, the amount necessary to constitute “atherapeutically effective amount” of a compound of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), mayvary from subject to subject.

The term “Bruton's tyrosine kinase,” as used herein, refers to Bruton'styrosine kinase from Homo sapiens, as disclosed in, e.g., U.S. Pat. No.6,326,469 (GenBank Accession No. NP_000052).

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of the compound of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), age, weight,general condition of the subject, the condition being treated, theseverity of the condition being treated, and the judgment of theprescribing physician. By way of example only, therapeutically effectiveamounts may be determined by routine experimentation, including but notlimited to a dose escalation clinical trial.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The term “identical,” as used herein, refers to two or more sequences orsubsequences which are the same. In addition, the term “substantiallyidentical,” as used herein, refers to two or more sequences which have apercentage of sequential units which are the same when compared andaligned for maximum correspondence over a comparison window, ordesignated region as measured using comparison algorithms or by manualalignment and visual inspection. By way of example only, two or moresequences may be “substantially identical” if the sequential units areabout 60% identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. Suchpercentages to describe the “percent identity” of two or more sequences.The identity of a sequence can exist over a region that is at leastabout 75-100 sequential units in length, over a region that is about 50sequential units in length, or, where not specified, across the entiresequence. This definition also refers to the complement of a testsequence. By way of example only, two or more polypeptide sequences areidentical when the amino acid residues are the same, while two or morepolypeptide sequences are “substantially identical” if the amino acidresidues are about 60% identical, about 65% identical, about 70%identical, about 75% identical, about 80% identical, about 85%identical, about 90% identical, or about 95% identical over a specifiedregion. The identity can exist over a region that is at least about75-100 amino acids in length, over a region that is about 50 amino acidsin length, or, where not specified, across the entire sequence of apolypeptide sequence. In addition, by way of example only, two or morepolynucleotide sequences are identical when the nucleic acid residuesare the same, while two or more polynucleotide sequences are“substantially identical” if the nucleic acid residues are about 60%identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. The identitycan exist over a region that is at least about 75-100 nucleic acids inlength, over a region that is about 50 nucleic acids in length, or,where not specified, across the entire sequence of a polynucleotidesequence.

The terms “inhibits”, “inhibiting”, or “inhibitor” of a kinase, as usedherein, refer to inhibition of enzymatic phosphotransferase activity.

The term “irreversible inhibitor,” as used herein, refers to a compoundthat, upon contact with a target protein (e.g., a kinase) causes theformation of a new covalent bond with or within the protein, whereby oneor more of the target protein's biological activities (e.g.,phosphotransferase activity) is diminished or abolished notwithstandingthe subsequent presence or absence of the irreversible inhibitor. Incontrast, a reversible inhibitor compound upon contact with a targetprotein does not cause the formation of a new covalent bond with orwithin the protein and therefore can associate and dissociate from thetarget protein.

The term “irreversible Btk inhibitor,” as used herein, refers to aninhibitor of Btk that can form a covalent bond with an amino acidresidue of Btk. In one embodiment, the irreversible inhibitor of Btk canform a covalent bond with a Cys residue of Btk; in particularembodiments, the irreversible inhibitor can form a covalent bond with aCys 481 residue of Btk or a cysteine residue in the homologouscorresponding position of another tyrosine kinase.

The term “isolated,” as used herein, refers to separating and removing acomponent of interest from components not of interest. Isolatedsubstances can be in either a dry or semi-dry state, or in solution,including but not limited to an aqueous solution. The isolated componentcan be in a homogeneous state or the isolated component can be a part ofa pharmaceutical composition that comprises additional pharmaceuticallyacceptable carriers and/or excipients. By way of example only, nucleicacids or proteins are “isolated” when such nucleic acids or proteins arefree of at least some of the cellular components with which it isassociated in the natural state, or that the nucleic acid or protein hasbeen concentrated to a level greater than the concentration of its invivo or in vitro production. Also, by way of example, a gene is isolatedwhen separated from open reading frames which flank the gene and encodea protein other than the gene of interest.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient which will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like. It isconsidered well within the skill of the art for one to determine suchprophylactically effective amounts by routine experimentation,including, but not limited to, a dose escalation clinical trial.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, Btk, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least 10, 50, 100, 250, 500, 1000 ormore times greater than the affinity for a non-target.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity relative to a non-targetactivity. In certain embodiments, specific modulater refers tomodulating a target activity at least 10, 50, 100, 250, 500, 1000 timesmore than a non-target activity.

The term “substantially purified,” as used herein, refers to a componentof interest that may be substantially or essentially free of othercomponents which normally accompany or interact with the component ofinterest prior to purification. By way of example only, a component ofinterest may be “substantially purified” when the preparation of thecomponent of interest contains less than about 30%, less than about 25%,less than about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 4%, less than about 3%, less than about 2%, orless than about 1% (by dry weight) of contaminating components. Thus, a“substantially purified” component of interest may have a purity levelof about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99% or greater.

The term “subject” as used herein, refers to an animal which is theobject of treatment, observation or experiment. By way of example only,a subject may be, but is not limited to, a mammal including, but notlimited to, a human.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is Btk.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of Btk, in an assay that measures suchresponse.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

DETAILED DESCRIPTION OF THE INVENTION

The methods described herein include administering to a subject in needa composition containing a therapeutically effective amount of one ormore reversible or irreversible Btk inhibitor compounds describedherein. Without being bound by theory, the diverse roles played by Btksignaling in various hematopoietic cell functions, e.g., B-cell receptoractivation, suggests that small molecule Btk inhibitors are useful forreducing the risk of or treating a variety of diseases affected by oraffecting many cell types of the hematopoetic lineage including, e.g.,autoimmune diseases, heteroimmune conditions or diseases, inflammatorydiseases, cancer (e.g., B-cell proliferative disorders), andthromboembolic disorders. Further, the irreversible Btk inhibitorcompounds described herein can be used to inhibit a small subset ofother tyrosine kinases that share homology with Btk by having a cysteineresidue (including a Cys 481 residue) that can form a covalent bond withthe irreversible inhibitor. Thus, a subset of tyrosine kinases otherthan Btk are also expected to be useful as therapeutic targets in anumber of health conditions.

In some embodiments, the methods described herein can be used to treatan autoimmune disease, which includes, but is not limited to, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barré syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitisis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, the methods described herein can be used to treatheteroimmune conditions or diseases, which include, but are not limitedto graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis.

In further embodiments, the methods described herein can be used totreat an inflammatory disease, which includes, but is not limited toasthma, inflammatory bowel disease, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In yet other embodiments, the methods described herein can be used totreat a cancer, e.g., B-cell proliferative disorders, which include, butare not limited to diffuse large B cell lymphoma, follicular lymphoma,chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrommacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In further embodiments, the methods described herein can be used totreat thromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine ^(©),” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojoumal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of reversible or irreversible Btkinhibitor compounds for treating any of the foregoing diseases.

For example, dosing of reversible or irreversible Btk inhibitorcompounds for treating an autoimmune disease can be assessed in a mousemodel of rheumatoid arthritis. In this model, arthritis is induced inBalb/c mice by administering anti-collagen antibodies andlipopolysaccharide. See Nandakumar et al. (2003), Am. J. Pathol163:1827-1837.

In another example, dosing of reversible or irreversible Btk inhibitorsfor the treatment of B-cell proliferative disorders can be examined in,e.g., a human-to-mouse xenograft model in which human B-cell lymphomacells (e.g. Ramos cells) are implanted into immunodefficient mice (e.g.,“nude” mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of the compound for one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivoBtk activity achieved by administering a given dose of an irreversibleBtk inhibitor. Cellular assays known in the art can be used to determinein vivo activity of Btk in the presence or absence of an irreversibleBtk inhibitor. For example, since activated Btk is phosphorylated attyrosine 223 (Y223) and tyrosine 551 (Y551), phospho-specificimmunocytochemical staining of P-Y223 or P-Y551-positive cells can beused to detect or quantify activation of Bkt in a population of cells(e.g., by FACS analysis of stained vs unstained cells). See, e.g.,Nisitani et al. (1999), Proc. Natl. Acad. Sci, USA 96:2221-2226. Thus,the amount of the Btk inhibitor compound that is administered to asubject can be increased or decreased as needed so as to maintain alevel of Btk inhibition optimal for treating the subject's diseasestate.

Compounds

In the following description of reversible or irreversible Btk compoundssuitable for use in the methods described herein, definitions ofreferred-to standard chemistry terms may be found in reference works (ifnot otherwise defined herein), including Carey and Sundberg “AdvancedOrganic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press,New York. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology, within the ordinary skill of the artare employed. In addition, nucleic acid and amino acid sequences for Btk(e.g., human Btk) are known in the art as disclosed in, e.g., U.S. Pat.No. 6,326,469. Unless specific definitions are provided, thenomenclature employed in connection with, and the laboratory proceduresand techniques of, analytical chemistry, synthetic organic chemistry,and medicinal and pharmaceutical chemistry described herein are thoseknown in the art. Standard techniques can be used for chemicalsyntheses, chemical analyses, pharmaceutical preparation, formulation,and delivery, and treatment of patients.

The Btk inhibitor compounds described herein are selective for Btk andkinases having a cysteine residue in an amino acid sequence position ofthe tyrosine kinase that is homologous to the amino acid sequenceposition of cysteine 481 in Btk. Inhibitor compounds described hereininclude a Michael acceptor moiety.

Generally, a reversible or irreversible inhibitor compound of Btk usedin the methods described herein is identified or characterized in an invitro assay, e.g., an acellular biochemical assay or a cellularfunctional assay. Such assays are useful to determine an in vitro IC₅₀for a reversible or irreversible Btk inhibitor compound.

For example, an acellular kinase assay can be used to determine Btkactivity after incubation of the kinase in the absence or presence of arange of concentrations of a candidate irreversible Btk inhibitorcompound. If the candidate compound is in fact an irreversible Btkinhibitor, Btk kinase activity will not be recovered by repeat washingwith inhibitor-free medium. See, e.g., J. B. Smaill, et al. (1999), J.Med. Chem. 42(10):1803-1815. Further, covalent complex formation betweenBtk and a candidate irreversible Btk inhibitor is a useful indicator ofirreversible inhibition of Btk that can be readily determined by anumber of methods known in the art (e.g., mass spectrometry). Forexample, some irreversible Btk-inhibitor compounds can form a covalentbond with Cys 481 of Btk (e.g., via a Michael reaction).

Cellular functional assays for Btk inhibition include measuring one ormore cellular endpoints in response to stimulating a Btk-mediatedpathway in a cell line (e.g., BCR activation in Ramos cells) in theabsence or presence of a range of concentrations of a candidateirreversible Btk inhibitor compound. Useful endpoints for determining aresponse to BCR activation include, e.g., autophosphorylation of Btk,phosphorylation of a Btk target protein (e.g., PLC-γ), and cytoplasmiccalcium flux.

High throughput assays for many acellular biochemical assays (e.g.,kinase assays) and cellular functional assays (e.g., calcium flux) arewell known to those of ordinary skill in the art. In addition, highthroughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments, Inc. Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass., etc.). These systems typically automate entire proceduresincluding all sample and reagent pipetting, liquid dispensing, timedincubations, and final readings of the microplate in detector(s)appropriate for the assay. Automated systems thereby allow theidentification and characterization of a large number of reversible orirreversible Btk compounds without undue effort.

Reversible or irreversible Btk inhibitor compounds can used for themanufacture of a medicament for treating any of the foregoing conditions(e.g., autoimmune diseases, inflammatory diseases, allergy disorders,B-cell proliferative disorders, or thromboembolic disorders).

In some embodiments, the reversible or irreversible Btk inhibitorcompound used for the methods described herein inhibits Btk activitywith an in vitro IC₅₀ of less than about 10 μM. (e.g., less than about 1μM, less than about 0.5 μM, less than about 0.4 μM, less than about 0.3μM, less than about 0.1, less than about 0.08 μM, less than about 0.06μM, less than about 0.05 μM, less than about 0.04 μM, less than about0.03 μM, less than about 0.02 μM, less than about 0.01, less than about0.008 μM, less than about 0.006 μM, less than about 0.005 μM, less thanabout 0.004 μM, less than about 0.003 μM, less than about 0.002 μM, lessthan about 0.001, less than about 0.00099 μM, less than about 0.00098μM, less than about 0.00097 μM, less than about 0.00096 μM, less thanabout 0.00095 μM, less than about 0.00094 μM, less than about 0.00093μM, less than about 0.00092, or less than about 0.00090 μM).

In one embodiment, the irreversible Btk inhibitor compound selectivelyand irreversibly inhibits an activated form of its target tyrosinekinase (e.g., a phosphorylated form of the tyrosine kinase). Forexample, activated Btk is transphosphorylated at tyrosine 551. Thus, inthese embodiments the irreversible Btk inhibitor inhibits the targetkinase in cells only once the target kinase is activated by thesignaling events.

Described herein are compounds of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), and (IIIc). Also described hereinare pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, pharmaceutically active metabolites, and pharmaceuticallyacceptable prodrugs of such compounds. Pharmaceutical compositions thatinclude at least one such compound or a pharmaceutically acceptablesalt, pharmaceutically acceptable solvate, pharmaceutically activemetabolite or pharmaceutically acceptable prodrug of such compound, areprovided. In some embodiments, when compounds disclosed herein containan oxidizable nitrogen atom, the nitrogen atom can be converted to anN-oxide by methods well known in the art. In certain embodiments,isomers and chemically protected forms of compounds having a structurerepresented by any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), and (IIIc), are also provided.

In a further embodiment are compounds having the structure of Formula(I):

wherein:

-   -   L_(a) is a bond, —CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂,        —CH₂S—, —N(R₂₁)—, —N(R₂₁)C(O)—, —C(O)N(R₂₁)—,        —N(R₂₁)C(O)N(R₂₁)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R₂₁)S(O)₂—, or        —S(O)₂N(R₂₁)—;    -   Ar is a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl;    -   R₃ is optionally substituted C₃-C₆ alkyl, substituted        cycloalkyl, optionally substituted aryl, optionally substituted        heteroaryl, —(C═O)C₁-C₆ alkyl, —(C═O)OR₄, —(C═O)NR₄R₄,        —(C═O)SR₄, -G-X, or

-   -   G is optionally substituted heterocycloalkyl, optionally        substituted aryl, or optionally substituted heteroaryl;    -   X is optionally substituted cycloalkyl; optionally substituted        heterocycloalkyl; optionally substituted aryl, optionally        substituted heteroaryl, —OR₄, —SR₄, or —NR₄R₄;    -   each R₄ is each independently H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl,        C₃-C₆ cycloalkyl, or C₂-C₆ heterocycloalkyl;    -   Y is an optionally substituted group selected from among alkyl,        heteroalkyl, cycloalkyl, aryl, and heteroaryl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   p is 0-2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, halogen, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (I) wherein L_(a) is bond,—CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—,—N(H)C(O)—, —C(O)N(H)—, —N(H)C(O)N(H)—, —O—, —S—, —S(O)—, —S(O)₂—,—N(H)S(O)₂—, or —S(O)₂N(H)—. In further embodiments, L_(a) is a bond,—CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—,—N(H)C(O)—, —C(O)N(H)—, —N(H)C(O)N(H)—, —O—, or —S—. In furtherembodiments, L_(a) is —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—, —O—, or—S—. In further embodiments, L_(a) is —OCH₂—, or —O—. In furtherembodiments, L_(a) is —OCH₂—. In further embodiments, L_(a) is —O—. Infurther embodiments, L_(a) is —CH₂O—. In further embodiments, L_(a) is—N(H)—. In further embodiments, L_(a) is —S—. In further embodiments,L_(a) is —CH₂—. In further embodiments, L_(a) is a bond.

In some embodiments is a compound of Formula (I) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In some embodiments is a compound of Formula (I) wherein R₃ isoptionally substituted C₃-C₆ alkyl, substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heteroaryl, -G-X, or

In some embodiments, R₃ is optionally substituted C₃-C₆ alkyl. In someembodiments, R₃ is substituted cycloalkyl. In some embodiments, R₃ isoptionally substituted optionally substituted optionally substitutedaryl. In some embodiments, R₃ is optionally substituted optionallysubstituted heteroaryl. In some embodiments, R₃ is -G-X. In someembodiments, G is aryl. In some embodiments, G is heteroaryl. In someembodiments, G is heterocycloalkyl. In further embodiments, G isselected from pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperizinyl,and morpholinyl. In some embodiments, G is pyrrolidinyl. In someembodiments, G is tetrahydrofuranyl. In some embodiments, G ispiperidinyl. In some embodiments, G is piperizinyl. In some embodiments,G is morpholinyl. In further embodiments, X is optionally substitutedheterocycloalkyl. In yet further embodiments, X is selected frompyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperizinyl, andmorpholinyl. In some embodiments, X is pyrrolidinyl. In someembodiments, X is tetrahydrofuranyl. In some embodiments, X ispiperidinyl. In some embodiments, X is piperizinyl. In some embodiments,X is morpholinyl. In further embodiments, X is —OR₄, —SR₄, or —NR₄R₄. Insome embodiments, X is —OR₄. In some embodiments, X is —SR₄. In someembodiments, X is —NR₄R₄. In yet a further embodiment, R₄ is eachindependently H or C₁-C₆ alkyl. In some embodiments, each R₄ is H. Insome embodiments, each R₄ is CH₃.

In another embodiment is a compound of Formula (I) wherein R₃ is

In further embodiments, Z is C(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂. Insome embodiments, Z is C(═O). In some embodiments, Z is NHC(═O). In someembodiments, Z is N(CH₃)C(═O). In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (I) wherein R₆, R₇ and R₈are H. In another embodiment is a compound of Formula (I) wherein R₇ andR₈ are H and R₆ is L-J-W. In a further embodiment, R₆ is H, substitutedor unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (I) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₆ and R₈ areH and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (I) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein R₆ and R₈ areH; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I), wherein W is H. In another embodiment of the aforementionedembodiments is a compound of Formula (I), wherein W is halogen. Inanother embodiment of the aforementioned embodiments is a compound ofFormula (I), wherein W is —CN. In another embodiment of theaforementioned embodiments is a compound of Formula (I), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In another embodiment, R₂₅ and R₂₆ aresubstituted or unsubstituted C₁-C₆ alkyl. In some embodiments, R₂₅ andR₂₆ are —CH₃. In another embodiment, R₂₅ and R₂₆ are substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In another embodiment, R₂₅ is H; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Inanother embodiment, R₂₅ is substituted or unsubstituted C₁-C₆ alkyl; andR₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In another embodiment embodiment is acompound of Formula (I), wherein R₂₅ and R₂₆ together with the nitrogento which they are attached form a heterocycloalkyl ring.

In another embodiment is a compound of Formula (I) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (I) wherein Y isoptionally substituted alkyl. In another embodiment, Y is optionallysubstituted heteroalkyl. In another embodiment, Y is optionallysubstituted cycloalkyl. In another embodiment, Y is optionallysubstituted heteroaryl. In another embodiment, Y is optionallysubstituted aryl. In a further embodiment, Y is phenyl.

In some embodiments is a compound of Formula (I) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In a further embodiment of the aforementioned embodiments is acompound of Formula (I), wherein p is 0. In some embodiments, p is 1. Insome embodiments, p is 2.

In a further embodiment are compounds having the structure of Formula(Ia):

wherein:

-   -   Ar is a substituted or unsubstituted aryl, or a substituted or        unsubstituted heteroaryl;    -   Z is C(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x), or        N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, halogen, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (Ia) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In some embodiments is a compound of Formula (Ia) wherein Z is C(═O),NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O). Insome embodiments, Z is NHC(═O). In some embodiments, Z is N(CH₃)C(═O).In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (Ia) wherein R₆, R₇ andR₈ are H. In another embodiment is a compound of Formula (Ia) wherein R₇and R₈ are H and R₆ is L-J-W. In a further embodiment, R₆ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (Ia) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (Ia) wherein R₆ and R₈are H and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (Ia) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₇is substituted or unsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In someembodiments, R₇ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (Ia) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ia), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (Ia), wherein W ishalogen. In another embodiment of the aforementioned embodiments is acompound of Formula (Ia), wherein W is —CN. In another embodiment of theaforementioned embodiments is a compound of Formula (Ia), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In another embodiment, R₂₅ and R₂₆ aresubstituted or unsubstituted C₁-C₆ alkyl. In some embodiments, R₂₅ andR₂₆ are —CH₃. In another embodiment, R₂₅ and R₂₆ are substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In another embodiment, R₂₅ is H; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Inanother embodiment, R₂₅ is substituted or unsubstituted C₁-C₆ alkyl; andR₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In another embodiment is a compoundof Formula (Ia), wherein R₂₅ and R₂₆ together with the nitrogen to whichthey are attached form a heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ia) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In some embodiments is a compound of Formula (Ia) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ia), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In a further embodiment are compounds having the structure of Formula(Ib):

wherein:

-   -   Ar is a substituted or unsubstituted aryl, or a substituted or        unsubstituted heteroaryl;    -   Z is C(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x), or        N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, halogen, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (Ib) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In some embodiments is a compound of Formula (Ib) wherein Z is C(═O),NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O). Insome embodiments, Z is NHC(═O). In some embodiments, Z is N(CH₃)C(═O).In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (Ib) wherein R₆, R₇ andR₈ are H. In another embodiment is a compound of Formula (Ib) wherein R₇and R₈ are H and R₆ is L-J-W. In a further embodiment, R₆ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (Ib) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (Ib) wherein R₆ and R₈are H and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (Ib) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (Ib) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Ib), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (Ib), wherein W ishalogen. In another embodiment of the aforementioned embodiments is acompound of Formula (Ib), wherein W is —CN. In another embodiment of theaforementioned embodiments is a compound of Formula (Ib), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In another embodiment, R₂₅ and R₂₆ aresubstituted or unsubstituted C₁-C₆ alkyl. In some embodiments, R₂₅ andR₂₆ are —CH₃. In another embodiment, R₂₅ and R₂₆ are substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In another embodiment, R₂₅ is H; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Inanother embodiment, R₂₅ is substituted or unsubstituted C₁-C₆ alkyl; andR₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In another embodiment is a compoundof Formula (Ib), wherein R₂₅ and R₂₆ together with the nitrogen to whichthey are attached form a heterocycloalkyl ring.

In another embodiment is a compound of Formula (Ib) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In some embodiments is a compound of Formula (Ib) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Ib), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In a further embodiment are compounds having the structure of Formula(II):

wherein:

-   -   L_(a) is a bond, —CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂,        —CH₂S—, —N(R₂₁)—, —N(R₂₁)C(O)—, —C(O)N(R₂₁)—,        —N(R₂₁)C(O)N(R₂₁)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R₂₁)S(O)₂—, or        —S(O)₂N(R₂₁)—;    -   Ar is a substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        aryl, or a substituted or unsubstituted heteroaryl;    -   R₃ is

-   -   Y is an optionally substituted heterocycloalkyl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   p is 0-2;    -   R₆ and R₈ are independently H or L-J, and R₇ is T-W; or    -   R₆ and R₇ are independently H or L-J, and R₈ is T-W; or    -   R₇ and R₈ are independently H or L-J, and R₆ is T-W; or    -   R₇ and R₈ taken together form a bond, and R₆ is T-W;    -   L is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   J is substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl,        NR₂₇R₂₈, or substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   T is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene, or        —S—;    -   W is NR₂₅R₂₆, —CN, substituted or unsubstituted C₃-C₆cycloalkyl,        or substituted or unsubstituted C-linked C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₆-C₁₂ aryl, or substituted or        unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or        substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₂-C₇ heterocycloalkyl, substituted or        unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl;    -   R₂₇ and R₂₈ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₇ and R₂₈ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (II) wherein L_(a) is bond,—CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—,—N(H)C(O)—, —C(O)N(H)—, —N(H)C(O)N(H)—, —O—, —S—, —S(O)—, —S(O)₂—,—N(H)S(O)₂—, or —S(O)₂N(H)—. In further embodiments, L_(a) is a bond,—CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—,—N(H)C(O)—, —C(O)N(H)—, —N(H)C(O)N(H)—, —O—, or —S—. In furtherembodiments, L_(a) is —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(H)—, —O—, or—S—. In further embodiments, L_(a) is —OCH₂—, or —O—. In furtherembodiments, L_(a) is —OCH₂—. In further embodiments, L_(a) is —O—. Infurther embodiments, L_(a) is —CH₂O—. In further embodiments, L_(a) is—N(H)—. In further embodiments, L_(a) is —S—. In further embodiments,L_(a) is —CH₂—. In further embodiments, L_(a) is a bond.

In some embodiments is a compound of Formula (II) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In another embodiment is a compound of Formula (II) wherein Z is C(═O),NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O). Insome embodiments, Z is NHC(═O). In some embodiments, Z is N(CH₃)C(═O).In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (II) wherein R₇ and R₈are H and R₆ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (II), wherein W is NR₂₅R₂₆. In a further embodiment,R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In some embodiments, R₂₅ and R₂₆ are cyclopropyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (II) wherein R₆ and R₈are H and R₇ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl.

In another embodiment is a compound of Formula (II) wherein R₇ and R₈taken together form a bond and R₆ is T-W. In a further embodiment, T isa bond, substituted or unsubstituted C₁-C₆alkylene, or substituted orunsubstituted C₃-C₆cycloalkylene. In some embodiments, T is a bond. Insome embodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene.In some embodiments, T is substituted or unsubstituted C₁-C₆alkylene. Ina further embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (II), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In some embodiments, R₂₅and R₂₆ are cyclopropyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (II) wherein Y isoptionally substituted pyrrolidinyl. In another embodiment is a compoundof Formula (II) wherein Y is optionally substituted piperidinyl.

In some embodiments is a compound of Formula (II) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In a further embodiment of the aforementioned embodiments is acompound of Formula (II), wherein p is 0. In some embodiments, p is 1.In some embodiments, p is 2.

In a further embodiment are compounds having the structure of Formula(IIa):

wherein:

-   -   Ar is a substituted or unsubstituted aryl, or a substituted or        unsubstituted heteroaryl;    -   Z is C(═O);    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   R₆ and R₈ are independently H or L-J, and R₇ is T-W; or    -   R₆ and R₇ are independently H or L-J, and R₈ is T-W; or    -   R₇ and R₈ are independently H or L-J, and R₆ is T-W; or    -   R₇ and R₈ taken together form a bond, and R₆ is T-W;    -   L is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   J is substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl,        NR₂₇R₂₈, or substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   T is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene, or        —S—;    -   W is NR₂₅R₂₆, —CN, substituted or unsubstituted C₃-C₆cycloalkyl,        or substituted or unsubstituted C-linked C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₆-C₁₂ aryl, or substituted or        unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or        substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₂-C₇ heterocycloalkyl, substituted or        unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl;    -   R₂₇ and R₂₈ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₇ and R₂₈ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (IIa) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In another embodiment is a compound of Formula (IIa) wherein R₇ and R₈are H and R₆ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (IIa), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is H and R₂₆ is cyclobutyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments, R₂₅ is —CH₃ andR₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (IIa) wherein R₆ and R₈are H and R₇ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl.

In another embodiment is a compound of Formula (IIa) wherein R₇ and R₈taken together form a bond and R₆ is T-W. In a further embodiment, T isa bond, substituted or unsubstituted C₁-C₆alkylene, or substituted orunsubstituted C₃-C₆cycloalkylene. In some embodiments, T is a bond. Insome embodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene.In some embodiments, T is substituted or unsubstituted C₁-C₆alkylene. Ina further embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIa), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In some embodiments, R₂₅and R₂₆ are cyclopropyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (IIa) wherein R₆ is H; R₈is —CN; and R₇ is L-J. In another embodiment is a compound of Formula(IIa) wherein R₆ is H; R₈ is —CN; and R₇ is C₃-C₆ cycloalkyl, C₆-C₁₂aryl, or C₃-C₁₂ heteroaryl. In another embodiment is a compound ofFormula (IIa) wherein R₆ is H; R₈ is —CN; and R₇ is cyclopropyl orphenyl.

In some embodiments is a compound of Formula (IIa) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIa), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In another embodiment are compounds having the structure of Formula(IIb):

wherein:

-   -   Ar is a substituted or unsubstituted aryl, or a substituted or        unsubstituted heteroaryl;    -   Z is C(═O);    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   R₂₁ and R₂₂ are each independently H, substituted or        unsubstituted C₁-C₆alkyl, or substituted or unsubstituted        C₃-C₈cycloalkyl;    -   R₂₃ is each independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   n is 0-4;    -   R₆ and R₈ are independently H or L-J, and R₇ is T-W; or    -   R₆ and R₇ are independently H or L-J, and R₈ is T-W; or    -   R₇ and R₈ are independently H or L-J, and R₆ is T-W; or    -   R₇ and R₈ taken together form a bond, and R₆ is T-W;    -   L is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   J is substituted or unsubstituted C₁-C₆ alkyl, substituted or        unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl,        NR₂₇R₂₈, or substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   T is a bond, substituted or unsubstituted C₁-C₆ alkylene,        substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or        unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted        C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene, or        —S—;    -   W is NR₂₅R₂₆, —CN, substituted or unsubstituted C₃-C₆cycloalkyl,        or substituted or unsubstituted C-linked C₂-C₇heterocycloalkyl,        substituted or unsubstituted C₆-C₁₂ aryl, or substituted or        unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, substituted        or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted        C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇        heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or        substituted or unsubstituted C₃-C₁₂ heteroaryl;    -   R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl,        substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or        unsubstituted C₂-C₇ heterocycloalkyl, substituted or        unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl;    -   R₂₇ and R₂₈ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₇ and R₂₈ together with the nitrogen to        which they are attached form a heterocycloalkyl ring;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (IIb) wherein Ar issubstituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In a further embodiment, Ar is substituted or unsubstitutedaryl. In yet a further embodiment, Ar is phenyl. In another embodiment,Ar is substituted or unsubstituted heteroaryl. In a further embodiment,Ar is indolyl, oxazolyl, furanyl, thienyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, or isoquinolinyl.

In another embodiment is a compound of Formula (IIb) wherein R₇ and R₈are H and R₆ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (IIb), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl,substituted or unsubstituted C₆-C₁₂ aryl, or substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is H and R₂₆ is cyclobutyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments, R₂₅ is —CH₃ andR₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (IIb) wherein R₆ and R₈are H and R₇ is T-W. In a further embodiment, T is a bond, substitutedor unsubstituted C₁-C₆alkylene, or substituted or unsubstitutedC₃-C₆cycloalkylene. In some embodiments, T is a bond. In someembodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene. Insome embodiments, T is substituted or unsubstituted C₁-C₆alkylene. In afurther embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂heteroaryl. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl.

In another embodiment is a compound of Formula (IIb) wherein R₇ and R₈taken together form a bond and R₆ is T-W. In a further embodiment, T isa bond, substituted or unsubstituted C₁-C₆alkylene, or substituted orunsubstituted C₃-C₆cycloalkylene. In some embodiments, T is a bond. Insome embodiments, T is substituted or unsubstituted C₃-C₆cycloalkylene.In some embodiments, T is substituted or unsubstituted C₁-C₆alkylene. Ina further embodiment, T is —CH₂—. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W issubstituted or unsubstituted C₃-C₆cycloalkyl, substituted orunsubstituted C-linked C₂-C₇heterocycloalkyl, substituted orunsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂heteroarylene. In some embodiments, W is substituted or unsubstitutedC₃-C₆cycloalkyl. In further embodiments, W is cyclopropyl. In someembodiments, W is substituted or unsubstituted C₆-C₁₂ aryl. In furtherembodiments, W is phenyl. In some embodiments, W is substituted orunsubstituted C₃-C₁₂ heteroaryl. In some embodiments, W is imidazolyl.In some embodiments, W is pyridinyl. In another embodiment of theaforementioned embodiments is a compound of Formula (IIb), wherein W isNR₂₅R₂₆. In a further embodiment, R₂₅ is H, substituted or unsubstitutedC₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆is substituted or unsubstituted C₃-C₆ cycloalkyl, substituted orunsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, orsubstituted or unsubstituted C₃-C₁₂ heteroaryl. In some embodiments, R₂₅and R₂₆ are cyclopropyl. In some embodiments, R₂₅ is H and R₂₆ iscyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclobutyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In someembodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl.

In another embodiment is a compound of Formula (IIb) wherein R₆ is H; R₈is —CN; and R₇ is L-J. In another embodiment is a compound of Formula(IIb) wherein R₆ is H; R₈ is —CN; and R₇ is C₃-C₆ cycloalkyl, C₆-C₁₂aryl, or C₃-C₁₂ heteroaryl. In another embodiment is a compound ofFormula (IIb) wherein R₆ is H; R₈ is —CN; and R₇ is cyclopropyl orphenyl.

In some embodiments is a compound of Formula (IIb) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIb), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In a further embodiment are compounds having the structure of Formula(III):

wherein:

-   -   A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl;    -   R₂₀ is H, halogen, —CN, —CF₃, —NO₂, —OH, substituted or        unsubstituted C₁-C₆alkyl, —N(R₂₁)C(═O)R₂₃, —C(═O)N(R₂₁)(R₂₂),        —O—(C₁-C₆alkyl), —O-alkylene-OR₂₁, —CO₂H, —O-alkylene-CO₂H,        —O-alkylene-C(═O)N(R₂₁)(R₂₂), or —N(R₂₁)C(═O)N(R₂₁)(R₂₂);    -   each R₂₁ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₂ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₃ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   p is 0-2;    -   n is 0-4;    -   R₃ is optionally substituted alkyl, optionally substituted        cycloalkyl, optionally substituted heterocycloalkyl, optionally        substituted aryl, optionally substituted heteroaryl, —(C═O)C₁-C₆        alkyl, —(C═O)OR₄, —(C═O)NR₄R₄, —(C═O)SR₄, -G-X, or

-   -   G is optionally substituted heterocycloalkyl, optionally        substituted aryl, or optionally substituted heteroaryl;    -   X is optionally substituted cycloalkyl; optionally substituted        heterocycloalkyl; optionally substituted aryl, optionally        substituted heteroaryl, —OR₄, —SR₄, or —NR₄R₄;    -   each R₄ is each independently H, C₁-C₆ alkyl, C₂-C₆ heteroalkyl,        C₃-C₆ cycloalkyl, or C₂-C₆ heterocycloalkyl;    -   Y is an optionally substituted group selected from among alkyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring; or a        pharmaceutically acceptable salt thereof.

In one embodiment is a compound of Formula (III) wherein A is aryl. In afurther embodiment, A is phenyl. In another embodiment is a compound ofFormula (III) wherein A is heteroaryl. In another embodiment is acompound of Formula (III) wherein A is cycloalkyl. In another embodimentis a compound of Formula (III) wherein A is heterocycloalkyl.

In another embodiment is a compound of Formula (III) wherein R₂₀ is H,halogen, —CN, —CF₃, —NO₂, —OH, or substituted or unsubstitutedC₁-C₆alkyl. In some embodiments, R₂₀ is H. In some embodiments, R₂₀ is—OH. In some embodiments, R₂₀ is —CN. In some embodiments, R₂₀ is —CF₃.In some embodiments, R₂₀ is halogen. In further embodiments, R₂₀ is F orCl. In some embodiments, R₂₀ is substituted or unsubstituted C₁-C₆alkyl.In some embodiments, R₂₀ is methyl. In some embodiments, R₂₀ is ethyl.In some embodiments, R₂₀ is isopropyl.

In another embodiment is a compound of Formula (III) wherein R₃ isoptionally substituted alkyl. In another embodiment is a compound ofFormula (III) wherein R₃ is optionally substituted cycloalkyl. Inanother embodiment is a compound of Formula (III) wherein R₃ isoptionally substituted heterocycloalkyl.

In another embodiment is a compound of Formula (III) wherein R₃ is -G-X.In some embodiments, G is aryl. In some embodiments, G is heteroaryl. Insome embodiments, G is heterocycloalkyl. In further embodiments, G isselected from pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperizinyl,and morpholinyl. In some embodiments, G is pyrrolidinyl. In someembodiments, G is tetrahydrofuranyl. In some embodiments, G ispiperidinyl. In some embodiments, G is piperizinyl. In some embodiments,G is morpholinyl. In a further embodiment is a compound of Formula (III)wherein X is optionally substituted cycloalkyl. In a further embodimentis a compound of Formula (III) wherein X is optionally substitutedheterocycloalkyl. In a further embodiment is a compound of Formula (III)wherein X is optionally substituted aryl. In a further embodiment is acompound of Formula (III) wherein X is optionally substitutedheteroaryl. In a further embodiment is a compound of Formula (III)wherein X is —OR₄. In a further embodiment is a compound of Formula(III) wherein X is —SR₄. In a further embodiment is a compound ofFormula (III) wherein X is —NR₄R₄.

In another embodiment is a compound of Formula (III) wherein R₃ is

In a further embodiment is a compound of Formula (III) wherein Z isC(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O).In some embodiments, Z is NHC(═O). In some embodiments, Z isN(CH₃)C(═O). In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (III) wherein R₃ is

and R₆, R₇ and R₈ are H. In a further embodiment is a compound ofFormula (III) wherein R₇ and R₈ are H and R₆ is L-J-W. In a furtherembodiment, R₆ is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (III) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₆ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (III) wherein R₃ is

R₆ and R₈ are H and R₇ is L-J-W. In a further embodiment, R₇ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (III) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₇ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is —CH₂N(CH₃)₂. In some embodiments, R₇ is

In another embodiment is a compound of Formula (III) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (III), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (III), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl. Inanother embodiment, R₂₅ and R₂₆ are substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₅ and R₂₆ are —CH₃. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In anotherembodiment embodiment is a compound of Formula (III), wherein R₂₅ andR₂₆ together with the nitrogen to which they are attached form aheterocycloalkyl ring.

In another embodiment is a compound of Formula (III) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is substitutedor unsubstituted ((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. Insome embodiments, R₆ is ((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (III) wherein Y isoptionally substituted alkyl. In another embodiment, Y is optionallysubstituted heteroalkyl. In another embodiment, Y is optionallysubstituted cycloalkyl. In another embodiment, Y is optionallysubstituted heteroaryl. In another embodiment, Y is optionallysubstituted aryl. In a further embodiment, Y is phenyl. In anotherembodiment, Y is optionally substituted heterocycloalkyl. In a furtherembodiment, Y is selected from

wherein m is 0 to 3. In another embodiment, Y is pyrrolidinyl. Inanother embodiment, Y is piperidinyl.

In some embodiments is a compound of Formula (III) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is halogen. In further embodiments, R₂₄ is F, Cl or Br.

In another embodiment of the aforementioned embodiments of Formula (III)wherein A is phenyl, is a compound wherein R₂₀ is attached to A at thepara position relative to the purinone ring. In another embodiment ofthe aforementioned embodiments of Formula (III) wherein A is phenyl, isa compound wherein R₂₀ is attached to A at the meta position relative tothe purinone ring. In another embodiment of the aforementionedembodiments of Formula (III) wherein A is phenyl, is a compound whereinR₂₀ is attached to A at the ortho position relative to the purinonering.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In a further embodiment of the aforementioned embodiments is acompound of Formula (III), wherein p is 0. In some embodiments, p is 1.In some embodiments, p is 2.

In a further embodiment are compounds having the structure of Formula(IIIa):

wherein:

-   -   R₂₀ is H, halogen, —CN, —CF₃, —NO₂, —OH, substituted or        unsubstituted C₁-C₆alkyl, —N(R₂₁)C(═O)R₂₃, —C(═O)N(R₂₁)(R₂₂),        —O—(C₁-C₆alkyl), —O-alkylene-OR₂₁, —CO₂H, —O-alkylene-CO₂H,        —O-alkylene-C(═O)N(R₂₁)(R₂₂), or —N(R₂₁)C(═O)N(R₂₁)(R₂₂);    -   each R₂₁ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₂ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₃ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   n is 0-4;    -   Z is C(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), or N(R₂₁)S(═O)_(x),        where x is 1 or 2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring; or a        pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (IIIa) wherein R₂₀ is H,halogen, —CN, —CF₃, —NO₂, —OH, or substituted or unsubstitutedC₁-C₆alkyl. In some embodiments, R₂₀ is H. In some embodiments, R₂₀ is—OH. In some embodiments, R₂₀ is —CN. In some embodiments, R₂₀ is —CF₃.In some embodiments, R₂₀ is halogen. In further embodiments, R₂₀ is F.In further embodiments, R₂₀ is Cl. In some embodiments, R₂₀ issubstituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₀ ismethyl. In some embodiments, R₂₀ is ethyl. In some embodiments, R₂₀ isisopropyl.

In another embodiment is a compound of Formula (IIIa) wherein Z isC(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O).In some embodiments, Z is NHC(═O). In some embodiments, Z isN(CH₃)C(═O). In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (IIIa) wherein R₆, R₇ andR₈ are H. In another embodiment is a compound of Formula (IIIa) whereinR₇ and R₈ are H and R₆ is L-J-W. In a further embodiment, R₆ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIa) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₆ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (IIIa) wherein R₆ and R₈are H and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIa) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₇ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is —CH₂N(CH₃)₂. In some embodiments, R₇ is

In some embodiments, R₇ is

In another embodiment is a compound of Formula (IIIa) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIIa), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (IIIa), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (IIIa), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl. Inanother embodiment, R₂₅ and R₂₆ are substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₅ and R₂₆ are —CH₃. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In anotherembodiment embodiment is a compound of Formula (IIIa), wherein R₂₅ andR₂₆ together with the nitrogen to which they are attached form aheterocycloalkyl ring.

In another embodiment is a compound of Formula (IIIa) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is substitutedor unsubstituted ((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. Insome embodiments, R₆ is ((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIa) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is substituted or unsubstituted alkoxy. In some embodiments, R₂₄ ismethoxy. In some embodiments, R₂₄ is halogen. In further embodiments,R₂₄ is F. In further embodiments, R₂₄ is Cl. In further embodiments, R₂₄is Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIIa), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In a further embodiment are compounds having the structure of Formula(IIIb):

wherein:

-   -   R₂₀ is H, halogen, —CN, —CF₃, —NO₂, —OH, substituted or        unsubstituted C₁-C₆alkyl, —N(R₂₁)C(═O)R₂₃, —C(═O)N(R₂₁)(R₂₂),        —O—(C₁-C₆alkyl), —O-alkylene-OR₂₁, —CO₂H, —O-alkylene-CO₂H,        —O-alkylene-C(═O)N(R₂₁)(R₂₂), or —N(R₂₁)C(═O)N(R₂₁)(R₂₂);    -   each R₂₁ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₂ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₃ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   n is 0-4;    -   Z is C(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), or N(R₂₁)S(═O)_(x),        where x is 1 or 2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring; or a        pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (IIIb) wherein R₂₀ is H,halogen, —CN, —CF₃, —NO₂, —OH, or substituted or unsubstitutedC₁-C₆alkyl. In some embodiments, R₂₀ is H. In some embodiments, R₂₀ is—OH. In some embodiments, R₂₀ is —CN. In some embodiments, R₂₀ is —CF₃.In some embodiments, R₂₀ is halogen. In further embodiments, R₂₀ is F.In further embodiments, R₂₀ is Cl. In some embodiments, R₂₀ issubstituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₀ ismethyl. In some embodiments, R₂₀ is ethyl. In some embodiments, R₂₀ isisopropyl.

In another embodiment is a compound of Formula (IIIb) wherein Z isC(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O).In some embodiments, Z is NHC(═O). In some embodiments, Z isN(CH₃)C(═O). In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (IIIb) wherein R₆, R₇ andR₈ are H. In another embodiment is a compound of Formula (IIIb) whereinR₇ and R₈ are H and R₆ is L-J-W. In a further embodiment, R₆ is H,substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIb) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₆ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (IIIb) wherein R₆ and R₈are H and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIb) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₇ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is —CH₂N(CH₃)₂. In some embodiments, R₇ is

In some embodiments, R₇ is

In another embodiment is a compound of Formula (IIIb) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIIb), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (IIIb), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (IIIb), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl. Inanother embodiment, R₂₅ and R₂₆ are substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₅ and R₂₆ are —CH₃. In another embodiment,R₂₅ and R₂₆ are substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ and R₂₆ are cyclopropyl. In another embodiment, R₂₅ isH; and R₂₆ is substituted or unsubstituted C₃-C₆ cycloalkyl. In someembodiments, R₂₅ is H and R₂₆ is cyclopropyl. In some embodiments, R₂₅is H and R₂₆ is cyclobutyl. In another embodiment, R₂₅ is substituted orunsubstituted C₁-C₆ alkyl; and R₂₆ is substituted or unsubstituted C₃-C₆cycloalkyl. In some embodiments, R₂₅ is —CH₃ and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is —CH₃ and R₂₆ is cyclobutyl. In anotherembodiment embodiment is a compound of Formula (IIIb), wherein R₂₅ andR₂₆ together with the nitrogen to which they are attached form aheterocycloalkyl ring.

In another embodiment is a compound of Formula (IIIb) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is substitutedor unsubstituted ((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. Insome embodiments, R₆ is ((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In some embodiments is a compound of Formula (IIIb) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is substituted or unsubstituted alkoxy. In some embodiments, R₂₄ ismethoxy. In some embodiments, R₂₄ is halogen. In further embodiments,R₂₄ is F. In further embodiments, R₂₄ is Cl. In further embodiments, R₂₄is Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIIb), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4.

In a further embodiment are compounds having the structure of Formula(IIIc):

wherein:

-   -   R₂₀ is H, halogen, —CN, —CF₃, —NO₂, —OH, substituted or        unsubstituted C₁-C₆alkyl, —N(R₂₁)C(═O)R₂₃, —C(═O)N(R₂₁)(R₂₂),        —O—(C₁-C₆alkyl), —O-alkylene-OR₂₁, —CO₂H, —O-alkylene-CO₂H,        —O-alkylene-C(═O)N(R₂₁)(R₂₂), or —N(R₂₁)C(═O)N(R₂₁)(R₂₂);    -   each R₂₁ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₂ is independently H, substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₃ is independently substituted or unsubstituted        C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl;    -   each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃,        —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃,        —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃,        —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂),        —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂),        substituted or unsubstituted alkyl, substituted or unsubstituted        alkoxy, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted heterocycloalkyl, or substituted or unsubstituted        cycloalkyl;    -   n is 0-4;    -   p is 0-2;    -   Y is an optionally substituted group selected from among        cycloalkyl, and heterocycloalkyl;    -   Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x),        or N(R₂₁)S(═O)_(x), where x is 1 or 2;    -   R₆ is H or L-J-W;    -   R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken        together form a bond;    -   L and J are each independently a bond, substituted or        unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆        cycloalkylene, substituted or unsubstituted C₁-C₆        heteroalkylene, substituted or unsubstituted C₂-C₇        heterocycloalkylene, substituted or unsubstituted C₆-C₁₂        arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene,        —CO—, —O—, or —S—;    -   W is H, —CN, or NR₂₅R₂₆;    -   R₂₅ and R₂₆ are each independently H, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆        cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl,        substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted        or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted        C₃-C₁₂ heteroaryl; or R₂₅ and R₂₆ together with the nitrogen to        which they are attached form a heterocycloalkyl ring; or a        pharmaceutically acceptable salt thereof.

In some embodiments is a compound of Formula (IIIc) wherein R₂₀ is H,halogen, —CN, —CF₃, —NO₂, —OH, or substituted or unsubstitutedC₁-C₆alkyl. In some embodiments, R₂₀ is H. In some embodiments, R₂₀ is—OH. In some embodiments, R₂₀ is —CN. In some embodiments, R₂₀ is —CF₃.In some embodiments, R₂₀ is halogen. In further embodiments, R₂₀ is F.In further embodiments, R₂₀ is Cl. In some embodiments, R₂₀ issubstituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₂₀ ismethyl. In some embodiments, R₂₀ is ethyl. In some embodiments, R₂₀ isisopropyl.

In another embodiment is a compound of Formula (IIIc) wherein Z isC(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂. In some embodiments, Z is C(═O).In some embodiments, Z is NHC(═O). In some embodiments, Z isN(CH₃)C(═O). In some embodiments, Z is S(═O)₂.

In another embodiment is a compound of Formula (IIIc) wherein R₆, R₇ andR₈ are H. In a another embodiment is a compound of Formula (IIIc)wherein R₇ and R₈ are H and R₆ is L-J-W. In a further embodiment, R₆ isH, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIc) wherein R₆ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₆ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₆ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (IIIc) wherein R₆ and R₈are H and R₇ is L-J-W. In a further embodiment, R₇ is H, substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In yet a further embodiment is acompound of Formula (IIIc) wherein R₇ is substituted or unsubstitutedC₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,(C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted substituted or unsubstitutedC₁-C₆heteroalkyl. In some embodiments, R₇ is substituted orunsubstituted (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₇ issubstituted or unsubstituted((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In someembodiments, R₇ is substituted or unsubstituted((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₇is —CH₂N(CH₃)₂. In some embodiments, R₇ is

In another embodiment is a compound of Formula (IIIc) wherein R₆ and R₈are H; R₇ is L-J-W; L is a bond, substituted or unsubstituted C₁-C₆alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J isa bond, substituted or unsubstituted C₁-C₆ alkylene, substituted orunsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene,substituted or unsubstituted C₆-C₁₂ arylene, or substituted orunsubstituted C₃-C₁₂ heteroarylene. In further embodiments, L is a bond.In further embodiments, L is substituted or unsubstituted C₃-C₆cycloalkylene. In further embodiments, L is substituted or unsubstitutedC₁-C₆ alkylene. In yet a further embodiment, L is —CH₂—. In furtherembodiments, J is substituted or unsubstituted C₁-C₆ alkylene,substituted or unsubstituted C₃-C₆ cycloalkylene, substituted orunsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, orsubstituted or unsubstituted C₃-C₁₂ heteroarylene. In some embodiments,J is substituted or unsubstituted C₁-C₆ alkylene. In furtherembodiments, J is —CH₂—. In some embodiments, J is substituted orunsubstituted C₁-C₆ cycloalkylene. In further embodiments, J iscyclopropyl. In some embodiments, J is substituted or unsubstitutedC₂-C₇ heterocycloalkylene. In further embodiments, J is pyrrolidinyl,piperidinyl, piperizinyl, morpholinyl, imidazolyl, or pyridiny. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIIc), wherein W is H. In another embodiment of theaforementioned embodiments is a compound of Formula (IIIc), wherein W is—CN. In another embodiment of the aforementioned embodiments is acompound of Formula (IIIc), wherein W is NR₂₅R₂₆. In a furtherembodiment, R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substitutedor unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstitutedC₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl. In someembodiments, R₂₅ and R₂₆ are —CH₃. In some embodiments, R₂₅ and R₂₆ arecyclopropyl. In some embodiments, R₂₅ is H and R₂₆ is cyclopropyl. Insome embodiments, R₂₅ is H and R₂₆ is cyclobutyl. In some embodiments,R₂₅ is —CH₃ and R₂₆ is cyclopropyl. In some embodiments, R₂₅ is —CH₃ andR₂₆ is cyclobutyl. In another embodiment is a compound of Formula(IIIc), wherein R₂₅ and R₂₆ together with the nitrogen to which they areattached form a heterocycloalkyl ring.

In another embodiment is a compound of Formula (IIIc) wherein R₇ and R₈taken together form a bond; and R₆ is L-J-W. In further embodiments, R₆is H, substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, substituted orunsubstituted C₁-C₆alkylC₃-C₆cycloalkyl, orC₁-C₄alkyl(C₂-C₇heterocycloalkyl). In further embodiments, R₆ issubstituted or unsubstituted C₁-C₆alkyl, substituted or unsubstitutedC₁-C₆heteroalkyl, (C₁-C₆dialkylamino)C₁-C₆alkyl,((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl, or((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. In some embodiments, R₆is substituted or unsubstituted C₁-C₆alkyl. In some embodiments, R₆ issubstituted or unsubstituted C₁-C₆heteroalkyl. In some embodiments, R₆is (C₁-C₆dialkylamino)C₁-C₆alkyl. In some embodiments, R₆ is substitutedor unsubstituted ((C₃-C₆cycloalkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl. Insome embodiments, R₆ is ((C₁-C₆alkyl)(C₃-C₆cycloalkyl)amino)C₁-C₆alkyl.

In another embodiment is a compound of Formula (IIIc) wherein Y isoptionally substituted cycloalkyl. In some embodiments, Y iscyclopentyl. In some embodiments, Y is cyclohexyl. In anotherembodiment, Y is optionally substituted heterocycloalkyl. In a furtherembodiment, Y is selected from

wherein m is 0 to 3. In another embodiment, Y is pyrrolidinyl. Inanother embodiment, Y is piperidinyl.

In some embodiments is a compound of Formula (IIIc) wherein R₂₄ is eachindependently halogen, —NH₂, —N(CH₃)₂, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted alkyl. In some embodiments, R₂₄ issubstituted or unsubstituted cycloalkyl. In some embodiments, R₂₄ issubstituted or unsubstituted heterocycloalkyl. In some embodiments, R₂₄is substituted or unsubstituted alkoxy. In some embodiments, R₂₄ ismethoxy. In some embodiments, R₂₄ is halogen. In further embodiments,R₂₄ is F. In further embodiments, R₂₄ is Cl. In yet further embodiments,R₂₄ is Br.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IIIc), wherein n is 0. In some embodiments, n is 1. In someembodiments, n is 2. In some embodiments, n is 3. In some embodiments, nis 4. In a further embodiment of the aforementioned embodiments is acompound of Formula (IIIc), wherein p is 0. In some embodiments, p is 1.In some embodiments, p is 2.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Further embodiments of compounds of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), and (IIIc) include, but are notlimited to, compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Further embodiments of compounds of Formula (I), (Ta), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), and (IIIc) include, but are notlimited to, compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Further embodiments of compounds of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), and (IIIc) include, but are notlimited to, compounds selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Further embodiments of compounds of Formula (I) or (II) include, but arenot limited to, compounds selected from the group consisting of:

Y Z R₇ n R₂₄

—C(═O)

0 —

—C(═O)

0 —

—C(═O)

1 3-OCH₃

—C(═O)

1 3-OCH₃

—C(═O)

0 —

—C(═O)

0 —

—C(═O)

1 3-OCH₃

—C(═O)

1 3-OCH₃

—N(H)C(═O)

0 —

—N(H)C(═O)

0 —

—N(H)C(═O)

1 3-OCH₃

—N(H)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

1 3-OCH₃

—C(═O)

0 —

—C(═O)

0 —

—C(═O)

1 3-OCH₃

—C(═O)

1 3-OCH₃

—C(═O)

0 —

—C(═O)

0 —

—C(═O)

1 3-OCH₃

—C(═O)

1 3-OCH₃

—C(═O)

0 —

—C(═O)

0 —

—C(═O)

1 3-OCH₃

—C(═O)

1 3-OCH₃

—N(H)C(═O)

0 —

—N(H)C(═O)

0 —

—N(H)C(═O)

1 3-OCH₃

—N(H)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

1 3-OCH₃

—N(H)C(═O)

0 —

—N(H)C(═O)

0 —

—N(H)C(═O)

1 3-OCH₃

—N(H)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

0 —

—N(CH₃)C(═O)

1 3-OCH₃

—N(CH₃)C(═O)

1 3-OCH₃or a pharmaceutically acceptable salt thereof.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

In some embodiments, the compounds of Formula (I), and (III) reversiblyinhibit Btk and in other embodiments are used to treat patientssuffering from Bruton's tyrosine kinase-dependent or Bruton's tyrosinekinase mediated conditions or diseases, including, but not limited to,cancer, autoimmune and other inflammatory diseases.

In some embodiments, the compounds of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), and (IIIc) irreversibly inhibit Btkand in other embodiments are used to treat patients suffering fromBruton's tyrosine kinase-dependent or Bruton's tyrosine kinase mediatedconditions or diseases, including, but not limited to, cancer,autoimmune and other inflammatory diseases.

Preparation of Compounds

Compounds of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc) may be synthesized using standard syntheticreactions known to those of skill in the art or using methods known inthe art. The reactions can be employed in a linear sequence to providethe compounds or they may be used to synthesize fragments which aresubsequently joined by the methods known in the art.

Described herein are compounds that inhibit the activity of tyrosinekinase(s), such as Btk, and processes for their preparation. Alsodescribed herein are pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically active metabolites andpharmaceutically acceptable prodrugs of such compounds. Pharmaceuticalcompositions that include at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, are provided.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). (all of which are incorporated by reference in their entirety).Other methods for the synthesis of compounds described herein may befound in International Patent Publication No. WO 01/01982901, Arnold etal. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170;Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002)1687-1690. General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

Further Forms of Compounds

Compounds disclosed herein have a structure of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). It is understoodthat when reference is made to compounds described herein, it is meantto include compounds of any of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc), as well as to all of thespecific compounds that fall within the scope of these generic formulae,unless otherwise indicated.

The compounds described herein may possess one or more stereocenters andeach center may exist in the R or S configuration. The compoundspresented herein include all diastereomeric, enantiomeric, and epimericforms as well as the appropriate mixtures thereof. Stereoisomers may beobtained, if desired, by methods known in the art as, for example, theseparation of stereoisomers by chiral chromatographic columns.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known, for example, by chromatography and/or fractionalcrystallization. In one embodiment, enantiomers can be separated bychiral chromatographic columns. In other embodiments, enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers, enantiomers, andmixtures thereof are considered as part of the compositions describedherein.

The methods and formulations described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), orpharmaceutically acceptable salts of compounds described herein, as wellas active metabolites of these compounds having the same type ofactivity. In some situations, compounds may exist as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In addition, the compounds described herein can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.

Compounds of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc) in unoxidized form can be prepared fromN-oxides of compounds of any of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc) by treating with a reducingagent, such as, but not limited to, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorustrichloride, tribromide, or the like in a suitable inert organicsolvent, such as, but not limited to, acetonitrile, ethanol, aqueousdioxane, or the like at 0 to 80° C.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, apharmaceutically active compound is modified such that the activecompound will be regenerated upon in vivo administration. The prodrugcan be designed to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound. (see, forexample, Nogrady (1985) Medicinal Chemistry A Biochemical Approach,Oxford University Press, New York, pages 388-392; Silverman (1992), TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.,San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein in their entirety.

Sites on the aromatic ring portion of compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) can besusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, such as, byway of example only, halogens can reduce, minimize or eliminate thismetabolic pathway.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulas and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, F, ³⁶Cl, respectively. Certainisotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Further,substitution with isotopes such as deuterium, i.e., ²H, can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect. In some embodiments, the metabolites of thecompounds described herein are N-oxides. In some embodiments themetabolites of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), and (IIIc) include, but are not limited to,compounds selected from the group consisting of:

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, andthe like; or with an organic acid such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like.

The corresponding counterions of the pharmaceutically acceptable saltsmay be analyzed and identified using various methods including, but notlimited to, ion exchange chromatography, ion chromatography, capillaryelectrophoresis, inductively coupled plasma, atomic absorptionspectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the followingtechniques: filtration, precipitation with a non-solvent followed byfiltration, evaporation of the solvent, or, in the case of aqueoussolutions, lyophilization.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

It should be understood that a reference to a salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UVIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Pharmaceutical Composition/Formulation

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, compounds of any ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc), with other chemical components, such as carriers, stabilizers,diluents, dispersing agents, suspending agents, thickening agents,and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. Preferably, the mammal is a human. A therapeutically effectiveamount can vary widely depending on the severity of the disease, the ageand relative health of the subject, the potency of the compound used andother factors. The compounds can be used singly or in combination withone or more therapeutic agents as components of mixtures.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In other embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compounddescribed herein, such as, for example, a compound of any of Formula(I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc),as an active ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (l) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

A “carrier” or “carrier materials” include any commonly used excipientsin pharmaceutics and should be selected on the basis of compatibilitywith compounds disclosed herein, such as, compounds of any of Formula(I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc),and the release profile properties of the desired dosage form. Exemplarycarrier materials include, e.g., binders, suspending agents,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, wetting agents, diluents, and the like.“Pharmaceutically compatible carrier materials” may include, but are notlimited to, acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

Combinations of one or more erosion facilitator with one or morediffusion facilitator can also be used in the present compositions.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, g, or ng of therapeutic agent per ml, dl, or 1 of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

Dosage Forms

The compositions described herein can be formulated for administrationto a subject via any conventional means including, but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular),buccal, intranasal, rectal or transdermal administration routes. As usedherein, the term “subject” is used to mean an animal, preferably amammal, including a human or non-human. The terms patient and subjectmay be used interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude a compound of any of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc) can be formulated into anysuitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions andthe like, for oral ingestion by a patient to be treated, solid oraldosage forms, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In other embodiments,the pharmaceutical formulation is in the form of a powder. In stillother embodiments, the pharmaceutical formulation is in the form of atablet, including but not limited to, a fast-melt tablet. Additionally,pharmaceutical formulations described herein may be administered as asingle capsule or in multiple capsule dosage form. In some embodiments,the pharmaceutical formulation is administered in two, or three, orfour, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofany of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc), with one or more pharmaceutical excipients to form abulk blend composition. When referring to these bulk blend compositionsas homogeneous, it is meant that the particles of the compound of any ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc), are dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms, such as tablets, pills, and capsules. The individual unit dosagesmay also include film coatings, which disintegrate upon oral ingestionor upon contact with diluent. These formulations can be manufactured byconventional pharmacological techniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

The pharmaceutical solid dosage forms described herein can include acompound described herein and one or more pharmaceutically acceptableadditives such as a compatible carrier, binder, filling agent,suspending agent, flavoring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof. In still other aspects, usingstandard coating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000), a film coating is providedaround the formulation of the compound of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). In oneembodiment, some or all of the particles of the compound of any ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc), are coated. In another embodiment, some or all of the particlesof the compound of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb),(III), (IIIa), (IIIb), or (IIIc), are microencapsulated. In stillanother embodiment, the particles of the compound of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), arenot microencapsulated and are uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), from a soliddosage form matrix as efficiently as possible, disintegrants are oftenused in the formulation, especially when the dosage forms are compressedwith binder. Disintegrants help rupturing the dosage form matrix byswelling or capillary action when moisture is absorbed into the dosageform. Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch such as National 1551or Amijel®, or sodium starch glycolate such as Promogel® or Explotab®, acellulose such as a wood product, methylcrystalline cellulose, e.g.,Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105, Elcema® P100,Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®, methylcellulose,croscarmellose, or a cross-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AqoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Formulators skilled in art can determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

The term “non water-soluble diluent” represents compounds typically usedin the formulation of pharmaceuticals, such as calcium phosphate,calcium sulfate, starches, modified starches and microcrystallinecellulose, and microcellulose (e.g., having a density of about 0.45g/cm³, e.g. Avicel, powdered cellulose), and talc.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms described herein. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

In other embodiments, one or more layers of the pharmaceuticalformulation are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compound of of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), from the formulation. Inother embodiments, the film coating aids in patient compliance (e.g.,Opadry® coatings or sugar coating). Film coatings including Opadry®typically range from about 1% to about 3% of the tablet weight. In otherembodiments, the compressed tablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), described above, insideof a capsule. In some embodiments, the formulations (non-aqueoussuspensions and solutions) are placed in a soft gelatin capsule. Inother embodiments, the formulations are placed in standard gelatincapsules or non-gelatin capsules such as capsules comprising HPMC. Inother embodiments, the formulation is placed in a sprinkle capsule,wherein the capsule may be swallowed whole or the capsule may be openedand the contents sprinkled on food prior to eating. In some embodiments,the therapeutic dose is split into multiple (e.g., two, three, or four)capsules. In some embodiments, the entire dose of the formulation isdelivered in a capsule form.

In various embodiments, the particles of the compound of any of Formula(I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc),and one or more excipients are dry blended and compressed into a mass,such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), which sufficientlyisolate the compound of any of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc), from other non-compatibleexcipients. Materials compatible with compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), arethose that delay the release of the compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), invivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds of any of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), may be formulated bymethods known by one of ordinary skill in the art. Such known methodsinclude, e.g., spray drying processes, spinning disk-solvent processes,hot melt processes, spray chilling methods, fluidized bed, electrostaticdeposition, centrifugal extrusion, rotational suspension separation,polymerization at liquid-gas or solid-gas interface, pressure extrusion,or spraying solvent extraction bath. In addition to these, severalchemical techniques, e.g., complex coacervation, solvent evaporation,polymer-polymer incompatibility, interfacial polymerization in liquidmedia, in situ polymerization, in-liquid drying, and desolvation inliquid media could also be used. Furthermore, other methods such asroller compaction, extrusion/spheronization, coacervation, ornanoparticle coating may also be used.

In one embodiment, the particles of compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), aremicroencapsulated prior to being formulated into one of the above forms.In still another embodiment, some or most of the particles are coatedprior to being further formulated by using standard coating procedures,such as those described in Remington's Pharmaceutical Sciences, 20thEdition (2000).

In other embodiments, the solid dosage formulations of the compounds ofany of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc), are plasticized (coated) with one or more layers.Illustratively, a plasticizer is generally a high boiling point solid orliquid. Suitable plasticizers can be added from about 0.01% to about 50%by weight (w/w) of the coating composition. Plasticizers include, butare not limited to, diethyl phthalate, citrate esters, polyethyleneglycol, glycerol, acetylated glycerides, triacetin, polypropyleneglycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearicacid, stearol, stearate, and castor oil.

In other embodiments, a powder including the formulations with acompound of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc), described herein, may be formulated toinclude one or more pharmaceutical excipients and flavors. Such a powdermay be prepared, for example, by mixing the formulation and optionalpharmaceutical excipients to form a bulk blend composition. Additionalembodiments also include a suspending agent and/or a wetting agent. Thisbulk blend is uniformly subdivided into unit dosage packaging ormulti-dosage packaging units.

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the compositions describedherein are added to water, the acids and the base react to liberatecarbon dioxide gas, thereby causing “effervescence.” Examples ofeffervescent salts include, e.g., the following ingredients: sodiumbicarbonate or a mixture of sodium bicarbonate and sodium carbonate,citric acid and/or tartaric acid. Any acid-base combination that resultsin the liberation of carbon dioxide can be used in place of thecombination of sodium bicarbonate and citric and tartaric acids, as longas the ingredients were suitable for pharmaceutical use and result in apH of about 6.0 or higher.

In other embodiments, the formulations described herein are soliddispersions. Methods of producing such solid dispersions are known inthe art and include, but are not limited to, for example, U.S. Pat. Nos.4,343,789, 5,340,591, 5,456,923, 5,700,485, 5,723,269, and U.S. Pub.Appl 2004/0013734, each of which is specifically incorporated byreference. In still other embodiments, the formulations described hereinare solid solutions. Solid solutions incorporate a substance togetherwith the active agent and other excipients such that heating the mixtureresults in dissolution of the drug and the resulting composition is thencooled to provide a solid blend which can be further formulated ordirectly added to a capsule or compressed into a tablet. Methods ofproducing such solid solutions are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 4,151,273, 5,281,420, and6,083,518, each of which is specifically incorporated by reference.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), can befurther formulated to provide a controlled release of the compound.Controlled release refers to the release of the compound of any ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc), from a dosage form in which it is incorporated according to adesired profile over an extended period of time. Controlled releaseprofiles include, for example, sustained release, prolonged release,pulsatile release, and delayed release profiles. In contrast toimmediate release compositions, controlled release compositions allowdelivery of an agent to a subject over an extended period of timeaccording to a predetermined profile. Such release rates can providetherapeutically effective levels of agent for an extended period of timeand thereby provide a longer period of pharmacologic response whileminimizing side effects as compared to conventional rapid release dosageforms. Such longer periods of response provide for many inherentbenefits that are not achieved with the corresponding short acting,immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In other embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media ofpH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein are deliveredusing a pulsatile dosage form. A pulsatile dosage form is capable ofproviding one or more immediate release pulses at predetermined timepoints after a controlled lag time or at specific sites. Pulsatiledosage forms including the formulations described herein, which includea compound of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc), may be administered using a variety ofpulsatile formulations known in the art. For example, such formulationsinclude, but are not limited to, those described in U.S. Pat. Nos.5,011,692, 5,017,381, 5,229,135, and 5,840,329, each of which isspecifically incorporated by reference. Other pulsatile release dosageforms suitable for use with the present formulations include, but arenot limited to, for example, U.S. Pat. Nos. 4,871,549, 5,260,068,5,260,069, 5,508,040, 5,567,441 and 5,837,284, all of which arespecifically incorporated by reference. In one embodiment, thecontrolled release dosage form is pulsatile release solid oral dosageform including at least two groups of particles, (i.e. multiparticulate)each containing the formulation described herein. The first group ofparticles provides a substantially immediate dose of the compound of anyof Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb),or (IIIc), upon ingestion by a mammal. The first group of particles canbe either uncoated or include a coating and/or sealant. The second groupof particles includes coated particles, which includes from about 2% toabout 75%, from about 2.5% to about 70%, or from about 40% to about 70%,by weight of the total dose of the compound of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), in saidformulation, in admixture with one or more binders. The coating includesa pharmaceutically acceptable ingredient in an amount sufficient toprovide a delay of from about 2 hours to about 7 hours followingingestion before release of the second dose. Suitable coatings includeone or more differentially degradable coatings such as, by way ofexample only, pH sensitive coatings (enteric coatings) such as acrylicresins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30DEudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100,Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D,Eudragit® NE 40D®) either alone or blended with cellulose derivatives,e.g., ethylcellulose, or non-enteric coatings having variable thicknessto provide differential release of the formulation that includes acompound of any of Formula (I).

Many other types of controlled release systems known to those ofordinary skill in the art and are suitable for use with the formulationsdescribed herein. Examples of such delivery systems include, e.g.,polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^(nd)Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983, each of which is specificallyincorporated by reference.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), described hereinand at least one dispersing agent or suspending agent for oraladministration to a subject. The formulations may be a powder and/orgranules for suspension, and upon admixture with water, a substantiallyuniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2^(nd) Ed., pp. 754-757(2002). In addition to the particles of compound of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), describedherein, the liquid dosage forms may include additives, such as: (a)disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) atleast one preservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102,Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, for example, hydrophilic polymers, electrolytes, Tween® 60 or80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMCK100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®,e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethyleneoxide and formaldehyde (also known as tyloxapol), poloxamers (e.g.,Pluronics F68®, F88®, and F108®, which are block copolymers of ethyleneoxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, alsoknown as Poloxamine 908®, which is a tetrafunctional block copolymerderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine (BASF Corporation, Parsippany, N.J.)). In otherembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein are known in the art and include, but are not limitedto, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethyleneglycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (UnionCarbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodiumlauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodiumtaurocholate, simethicone, phosphotidylcholine and the like

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Inone embodiment, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.001% toabout 1.0% the volume of the aqueous dispersion. In another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.005% to about0.5% the volume of the aqueous dispersion. In yet another embodiment,the aqueous liquid dispersion can comprise a sweetening agent orflavoring agent in a concentration ranging from about 0.01% to about1.0% the volume of the aqueous dispersion.

In addition to the additives listed above, the liquid formulations canalso include inert diluents commonly used in the art, such as water orother solvents, solubilizing agents, and emulsifiers. Exemplaryemulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodiumdoccusate, cholesterol, cholesterol esters, taurocholic acid,phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

In some embodiments, the pharmaceutical formulations described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563, each of which is specifically incorporated by reference.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein. The amounts ofsuch additives can be readily determined by one skilled in the art,according to the particular properties desired.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations thatinclude a compound of any of Formula (I), (Ia), (Ib), (II), (IIa),(IIb), (III), (IIIa), (IIIb), or (IIIc), which are prepared according tothese and other techniques well-known in the art are prepared assolutions in saline, employing benzyl alcohol or other suitablepreservatives, fluorocarbons, and/or other solubilizing or dispersingagents known in the art. See, for example, Ansel, H. C. et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995).Preferably these compositions and formulations are prepared withsuitable nontoxic pharmaceutically acceptable ingredients. Theseingredients are known to those skilled in the preparation of nasaldosage forms and some of these can be found in REMINGTON: THE SCIENCEAND PRACTICE OF PHARMACY, 21st edition, 2005, a standard reference inthe field. The choice of suitable carriers is highly dependent upon theexact nature of the nasal dosage form desired, e.g., solutions,suspensions, ointments, or gels. Nasal dosage forms generally containlarge amounts of water in addition to the active ingredient. Minoramounts of other ingredients such as pH adjusters, emulsifiers ordispersing agents, preservatives, surfactants, gelling agents, orbuffering and other stabilizing and solubilizing agents may also bepresent. The nasal dosage form should be isotonic with nasal secretions.

For administration by inhalation, the compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc),described herein may be in a form as an aerosol, a mist or a powder.Pharmaceutical compositions described herein are conveniently deliveredin the form of an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compounddescribed herein and a suitable powder base such as lactose or starch.

Buccal Formulations

Buccal formulations that include compounds of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), may beadministered using a variety of formulations known in the art. Forexample, such formulations include, but are not limited to, U.S. Pat.Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, each of which isspecifically incorporated by reference. In addition, the buccal dosageforms described herein can further include a bioerodible (hydrolysable)polymeric carrier that also serves to adhere the dosage form to thebuccal mucosa. The buccal dosage form is fabricated so as to erodegradually over a predetermined time period, wherein the delivery of thecompound of any of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc), is provided essentially throughout. Buccaldrug delivery, as will be appreciated by those skilled in the art,avoids the disadvantages encountered with oral drug administration,e.g., slow absorption, degradation of the active agent by fluids presentin the gastrointestinal tract and/or first-pass inactivation in theliver. With regard to the bioerodible (hydrolysable) polymeric carrier,it will be appreciated that virtually any such carrier can be used, solong as the desired drug release profile is not compromised, and thecarrier is compatible with the compound of any of Formula (I), (Ia),(Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), and anyother components that may be present in the buccal dosage unit.Generally, the polymeric carrier comprises hydrophilic (water-solubleand water-swellable) polymers that adhere to the wet surface of thebuccal mucosa. Examples of polymeric carriers useful herein includeacrylic acid polymers and co, e.g., those known as “carbomers”(Carbopol®, which may be obtained from B.F. Goodrich, is one suchpolymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144, each of which is specifically incorporated by reference inits entirety.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiment, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofany of Formula (I), (II), or (III); (2) a penetration enhancer; and (3)an aqueous adjuvant. In addition, transdermal formulations can includeadditional components such as, but not limited to, gelling agents,creams and ointment bases, and the like. In some embodiments, thetransdermal formulation can further include a woven or non-woven backingmaterial to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds of any of Formula (I),(Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc). Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Injectable Formulations

Formulations that include a compound of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), suitable forintramuscular, subcutaneous, or intravenous injection may includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Other Formulations

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the inhibition of Btk or a homolog thereof, or for thetreatment of diseases or conditions that would benefit, at least inpart, from inhibition of Btk. In addition, a method for treating any ofthe diseases or conditions described herein in a subject in need of suchtreatment, involves administration of pharmaceutical compositionscontaining at least one compound of any of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), described herein,or a pharmaceutically acceptable salt, pharmaceutically acceptableN-oxide, pharmaceutically active metabolite, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate thereof, intherapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, or from about 1-1500 mg per day. The desireddose may conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosage appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein is about 1 mg per day. In another embodiment,the daily dosage appropriate for the compound of Formula (I), (II) or(III), or a pharmaceutically acceptable salt thereof, described hereinis about 2 mg per day. In another embodiment, the daily dosageappropriate for the compound of Formula (I), (II) or (III), or apharmaceutically acceptable salt thereof, described herein is about 5 mgper day. In another embodiment, the daily dosage appropriate for thecompound of Formula (I), (II) or (III), or a pharmaceutically acceptablesalt thereof, described herein is about 10 mg per day. In anotherembodiment, the daily dosage appropriate for the compound of Formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof,described herein is about 20 mg per day. In another embodiment, thedaily dosage appropriate for the compound of Formula (I), (II) or (III),or a pharmaceutically acceptable salt thereof, described herein is about30 mg per day. In another embodiment, the daily dosage appropriate forthe compound of Formula (I), (II) or (III), or a pharmaceuticallyacceptable salt thereof, described herein is about 40 mg per day. Inanother embodiment, the daily dosage appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein is about 50 mg per day. In another embodiment,the daily dosage appropriate for the compound of Formula (I), (II) or(III), or a pharmaceutically acceptable salt thereof, described hereinis about 60 mg per day. In another embodiment, the daily dosageappropriate for the compound of Formula (I), (II) or (III), or apharmaceutically acceptable salt thereof, described herein is about 70mg per day. In another embodiment, the daily dosage appropriate for thecompound of Formula (I), (II) or (III), or a pharmaceutically acceptablesalt thereof, described herein is about 80 mg per day. In anotherembodiment, the daily dosage appropriate for the compound of Formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof,described herein is about 90 mg per day. In another embodiment, thedaily dosage appropriate for the compound of Formula (I), (II) or (III),or a pharmaceutically acceptable salt thereof, described herein is about100 mg per day. In another embodiment, the daily dosage appropriate forthe compound of Formula (I), (II) or (III), or a pharmaceuticallyacceptable salt thereof, described herein is about 150 mg per day. Inanother embodiment, the daily dosage appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein is about 200 mg per day. In anotherembodiment, the daily dosage appropriate for the compound of Formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof,described herein is about 250 mg per day. In another embodiment, thedaily dosage appropriate for the compound of Formula (I), (II) or (III),or a pharmaceutically acceptable salt thereof, described herein is about300 mg per day. In another embodiment, the daily dosage appropriate forthe compound of Formula (I), (II) or (III), or a pharmaceuticallyacceptable salt thereof, described herein is about 350 mg per day. Inanother embodiment, the daily dosage appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein is about 400 mg per day. In anotherembodiment, the daily dosage appropriate for the compound of Formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof,described herein is about 500 mg per day. In another embodiment, thedaily dosage appropriate for the compound of Formula (I), (II) or (III),or a pharmaceutically acceptable salt thereof, described herein is about600 mg per day. In another embodiment, the daily dosage appropriate forthe compound of Formula (I), (II) or (III), or a pharmaceuticallyacceptable salt thereof, described herein is about 700 mg per day. Inanother embodiment, the daily dosage appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein is about 800 mg per day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, described herein are from about 0.01 to about 50 mg/kg per bodyweight.

In some embodiments, the daily dosage or the amount of active in thedosage form are lower or higher than the ranges indicated herein, basedon a number of variables in regard to an individual treatment regime. Invarious embodiments, the daily and unit dosages are altered depending ona number of variables including, but not limited to, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The reversible or irreversible Btk inhibitor compositions describedherein can also be used in combination with other well known therapeuticreagents that are selected for their therapeutic value for the conditionto be treated. In general, the compositions described herein and, inembodiments where combinational therapy is employed, other agents do nothave to be administered in the same pharmaceutical composition, and may,because of different physical and chemical characteristics, have to beadministered by different routes. The determination of the mode ofadministration and the advisability of administration, where possible,in the same pharmaceutical composition, is well within the knowledge ofthe skilled clinician. The initial administration can be made accordingto established protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

In certain instances, it may be appropriate to administer at least onereversible or irreversible Btk inhibitor compound described herein incombination with another therapeutic agent. By way of example only, ifone of the side effects experienced by a patient upon receiving one ofthe reversible or irreversible Btk inhibitor compounds described hereinis nausea, then it may be appropriate to administer an anti-nausea agentin combination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may have minimal therapeutic benefit, but in combinationwith another therapeutic agent, the overall therapeutic benefit to thepatient is enhanced). Or, by way of example only, the benefitexperienced by a patient may be increased by administering one of thecompounds described herein with another therapeutic agent (which alsoincludes a therapeutic regimen) that also has therapeutic benefit. Inany case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literatureCombination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb),or (IIIc) described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; theuse of multiple therapeutic combinations are also envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms, withinthe first 6 hours of the onset of the symptoms, or within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. A compound should be administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. The length oftreatment can vary for each subject, and the length can be determinedusing the known criteria. For example, the compound or a formulationcontaining the compound can be administered for at least 2 weeks,between about 1 month to about 5 years, or from about 1 month to about 3years.

Exemplary Therapeutic Agents for Use in Combination with a Reversible orIrreversible Btk Inhibitor Compound

Where the subject is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease, areversible or irreversible Btk inhibitor compound can be used in withone or more of the following therapeutic agents in any combination:immunosuppressants (e.g., tacrolimus, cyclosporin, rapamicin,methotrexate, cyclophosphamide, azathioprine, mercaptopurine,mycophenolate, or FTY720), glucocorticoids (e.g., prednisone, cortisoneacetate, prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific inhibitors (e.g., valdecoxib,celecoxib, or rofecoxib), leflunomide, gold thioglucose, goldthiomalate, aurofin, sulfasalazine, hydroxychloroquinine, minocycline,TNF-α binding proteins (e.g., infliximab, etanercept, or adalimumab),abatacept, anakinra, interferon-β, interferon-γ, interleukin-2, allergyvaccines, antihistamines, antileukotrienes, beta-agonists, theophylline,or anticholinergics.

Where the subject is suffering from or at risk of suffering from aB-cell proliferative disorder (e.g., plasma cell myeloma), the subjectcan be treated with a reversible or irreversible Btk inhibitor compoundin any combination with one or more other anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossyphol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Further examples of anti-cancer agents for use in combination with areversible or irreversible Btk inhibitor compound include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Other anti-cancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include Adriamycin,Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflomithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin Il (including recombinant interleukin II, or rlL2),interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferonalfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase;peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman;piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimersodium; porfiromycin; prednimustine; procarbazine hydrochloride;puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide;safingol; safingol hydrochloride; semustine; simtrazene; sparfosatesodium; sparsomycin; spirogermanium hydrochloride; spiromustine;spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin;tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin;teniposide; teroxirone; testolactone; thiamiprine; thioguanine;thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestoloneacetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate;triptorelin; tubulozole hydrochloride; uracil mustard; uredepa;vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include: 20-epi-1, 25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;9-dioxamycin; diphenyl spiromustine; docosanol; dolasetron;doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;ecomustine; edelfosine; edrecolomab; eflomithine; elemene; emitefur;epirubicin; epristeride; estramustine analogue; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin;pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine;pegaspargase; pegfilgrastim; peldesine; pentosan polysulfate sodium;pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; porfimer sodium; porfiromycin;prednisone; propyl bis-acridone; prostaglandin J2; proteasomeinhibitors; protein A-based immune modulator; protein kinase Cinhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerieconjugate; raf antagonists; raltitrexed; ramosetron; ras famesyl proteintransferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptinedemethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RIIretinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; signal transductionmodulators; single chain antigen-binding protein; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Yet other anticancer agents that can be employed in combination with areversible or irreversible Btk inhibitor compound include alkylatingagents, antimetabolites, natural products, or hormones, e.g., nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.),alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine,lomusitne, ete.), or triazenes (decarbazine, etc.). Examples ofantimetabolites include but are not limited to folic acid analog (e.g.,methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs(e.g., mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with a reversible orirreversible Btk inhibitor compound include but are not limited to vincaalkaloids (e.g., vinblastin, vincristine), epipodophyllotoxins (e.g.,etoposide), antibiotics (e.g., daunorubicin, doxorubicin, bleomycin),enzymes (e.g., L-asparaginase), or biological response modifiers (e.g.,interferon alpha).

Examples of alkylating agents that can be employed in combination areversible or irreversible Btk inhibitor compound include, but are notlimited to, nitrogen mustards (e.g., mechloroethamine, cyclophosphamide,chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, ete.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with areversible or irreversible Btk inhibitor compound include, but are notlimited to, adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with a reversible or irreversible Btk inhibitor compoundinclude without limitation the following marketed drugs and drugs indevelopment: Erbulozole (also known as R-55104), Dolastatin 10 (alsoknown as DLS-10 and NSC-376128), Mivobulin isethionate (also known asCI-980), Vincristine, NSC-639829, Discodermolide (also known asNVP-XX-A-296), ABT-751 (Abbott, also known as E-7010), Altorhyrtins(such as Altorhyrtin A and Altorhyrtin C), Spongistatins (such asSpongistatin 1, Spongistatin 2, Spongistatin 3, Spongistatin 4,Spongistatin 5, Spongistatin 6, Spongistatin 7, Spongistatin 8, andSpongistatin 9), Cemadotin hydrochloride (also known as LU-103793 andNSC-D-669356), Epothilones (such as Epothilone A, Epothilone B,Epothilone C (also known as desoxyepothilone A or dEpoA), Epothilone D(also referred to as KOS-862, dEpoB, and desoxyepothilone B), EpothiloneE, Epothilone F, Epothilone B N-oxide, Epothilone A N-oxide,16-aza-epothilone B, 21-aminoepothilone B (also known as BMS-310705),21-hydroxyepothilone D (also known as Desoxyepothilone F and dEpoF),26-fluoroepothilone), Auristatin PE (also known as NSC-654663),Soblidotin (also known as TZT-1027), LS-4559-P (Pharmacia, also known asLS-4577), LS-4578 (Pharmacia, also known as LS-477-P), LS-4477(Pharmacia), LS-4559 (Pharmacia), RPR-112378 (Aventis), Vincristinesulfate, DZ-3358 (Daiichi), FR-182877 (Fujisawa, also known asWS-9885B), GS-164 (Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy ofSciences), BSF-223651 (BASF, also known as ILX-651 and LU-223651),SAH-49960 (Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97(Armad/Kyowa Hakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko),IDN-5005 (Indena), Cryptophycin 52 (also known as LY-355703), AC-7739(Ajinomoto, also known as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto,also known as AVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A),Vitilevuamide, Tubulysin A, Canadensol, Centaureidin (also known asNSC-106969), T-138067 (Tularik, also known as T-67, TL-138067 andTI-138067), COBRA-1 (Parker Hughes Institute, also known as DDE-261 andWHI-261), H10 (Kansas State University), H16 (Kansas State University),Oncocidin A1 (also known as BTO-956 and DIME), DDE-313 (Parker HughesInstitute), Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute),SPA-1 (Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-1AABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-115781 (Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (-)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated witha reversible or irreversible Btk inhibitor compound in any combinationwith one or more other anti-thromboembolic agents. Examples ofanti-thromboembolic agents include, but are not limited any of thefollowing: thrombolytic agents (e.g., alteplase anistreplase,streptokinase, urokinase, or tissue plasminogen activator), heparin,tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xainhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a,otamixaban, LY517717, or YM150), ticlopidine, clopidogrel, CS-747(prasugrel, LY640315), ximelagatran, or BIBR 1048.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease, disorder, or condition that wouldbenefit by inhibition of Btk, or in which Btk is a mediator orcontributor to the symptoms or cause.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

EXAMPLES

The following specific and non-limiting examples are to be construed asmerely illustrative, and do not limit the present disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentdisclosure to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety. Where reference ismade to a URL or other such identifier or address, it is understood thatsuch identifiers can change and particular information on the internetcan come and go, but equivalent information can be found by searchingthe internet. Reference thereto evidences the availability and publicdissemination of such information.

Example 1 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(8)

To a stirred solution of 4,6-dichloro-5-nitropyrimidine (7 g, 36 mmol)and TEA (10 mL, 72 mmol) in DCM (60 mL) at 0° C. under N₂ was addedBn₂NH in DCM (10 mL) dropwise over 2 hrs. Stirring was continued for 30min before the reaction mixture was diluted with water (100 mL). Thelayers were separated and the aqueous layer was extracted with DCM (50mL×3). The combined organic layer was washed with water (100 mL×2) andbrine (100 mL×1), dried over Na₂SO₄ and concentrated in vacuo.N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (12.8 g, 100%) wasobtained as a brown slurry. LC-MS (ESI): m/z (M+1) 355.

To a solution of N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7.0g, 19.7 mmol) and TEA (5.5 mL, 40 mmol) in dioxane (100 mL) was addedtert-butyl 3-aminophenylcarbamate (4.2 g, 20.0 mmol). The reactionmixture was heated to 70° C. for 6 hrs under N₂. After the reaction wascooled down to room temperature, water (150 mL) was introduced. Thelayers were separated and the aqueous layer was extracted with EtOAc (50mL×2). The combined organic layer was washed with water (150 mL×2) andbrine (100 mL×1), dried over Na₂SO₄ and concentrated to dryness.tert-Butyl 3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenylcarbamate (2) (9.2 g, 88%) was obtained as a brown solid. LC-MS(ESI): m/z (M+1) 527.

To a solution of tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino) phenylcarbamate (2)(9.2 g, 17.5 mmol) in 100 mL THF were added Fe powder (9.8 g, 175 mmol),NH₄Cl (18.7 g, 350 mmol), 100 mL MeOH and 20 mL H₂O. The reactionmixture was heated at 50° C. for 7 hrs under N₂. After cooling to rt,the reaction mixture was filtered through a pad of Celite. The filtratewas concentrated to 100 mL, and extracted with EtOAc (80 mL×3). Thecombined organic layer was washed with water (100 mL×2) and brine (100mL×1), dried over Na₂SO₄, then concentrated to dryness in vacuo. Theresidual was purified by column chromatography (silica gel, 0 to 30%ethyl acetate in petroleum ether) to give tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenylcarbamate (3) (4.0g, 46.1%) as a brown solid. LC-MS (ESI): m/z (M+1) 497.

A solution of tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino) phenylcarbamate (3)(4.0 g, 8.1 mmol) and TEA (2 mL, 14.5 mmol) in 80 mL dry DCM was cooledto 0° C. under N₂, triphosgene (1.2 g, 4.0 mmol) in 10 mL dry DCM wasadded dropwise during 2 hrs. After additional 1 hr stirring, thereaction was quenched with water (100 mL). The organic layer wasseparated, washed with water (100 mL×2) and brine (100 mL×1), dried overNa₂SO₄, then concentrated to dryness in vacuo. tert-Butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (4) (3.0 g,71%) was obtained as a brown solid. LC-MS (ESI): m/z (M+1) 523.

To a mixture of tert-butyl 3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (4) (3.0 g, 5.7 mmol) in 120 mL MeOH was added 3.0 gPd(OH)₂/C (20 wt %) and 6 drops of con. HCl. After two vacuum/H₂ cyclesto remove air from the reaction flask, the stirred mixture was heated at60° C. under hydrogen atmosphere overnight. The reaction mixture wasfiltered through a Celite pad and the filtrate was concentrated todryness in vacuo. The residue was purified by column chromatography(silica gel, 0 to 5% methanol in DCM) to give tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (1.5 g, 76%) as awhite solid. LC-MS (ESI): m/z (M+1) 343.

To a stirred mixture of tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (600 mg, 1.8mmol) and 400 mg 4 Å MS in 16 mL dry DMF were added4-phenoxyphenylboronic acid (1.05 g, 4.9 mmol), Cu(OAc)₂ (320 mg, 1.8mmol) and pyridine (1 mL, 12.7 mmol). The reaction mixture was heated at37° C. for 5 hrs under an O₂ atmosphere. After cooling down to rt, thereaction mixture was filtered through a Celite pad. The filtrate wasdiluted with water (100 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layer was washed with water (100 mL×2) and brine (100mL×1), dried over Na₂SO₄, then concentrated to dryness. The residue waspurified by column chromatography (silica gel, 0 to 5% methanol in DCM)to give tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl) phenylcarbamate(6) (404 mg, 45%) as a brown solid. LC-MS (ESI): m/z (M+1) 511.

To a solution of tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl) phenylcarbamate(6) (404 mg, 0.8 mmol) in 8 mL DCM was added 2 mL TFA dropwise. Thereaction mixture was stirred at rt for 1 hr, then concentrated todryness. The residue was purified by column chromatography (silica gel,0 to 5% methanol in DCM (0.3% Et₃N)) to give6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7)(325 mg, 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 411.

To a mixture of 4-(dimethylamino)but-2-enoic acid hydrochloride (81 mg,0.49 mmol) and 1 drop of DMF in 3 mL dry CH₃CN was added 0.5 mL oxalylchloride dropwise under N₂. The reaction mixture was stirred at rt for 1hr, then concentrated to dryness in vacuo. The resulting solid wasdissolved in 2 mL dry DCM and was transferred to a stirred solution of6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7)(100 mg, 0.24 mmol) and one drop of TEA in 3 mL dry DCM in an ice-waterbath. After stirring for 2 hrs, the reaction was quenched with MeOH. Theresulting mixture was concentrated to dry, pre-purified by columnchromatography (silica gel, 0 to 5% methanol in DCM), followed by Gilsonusing 10 to 95% acetonitrile in water (0.1% TFA) to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(8) (61 mg, 48%) as a white solid. ¹H NMR (400 MHz, DMSO) δ 10.56 (s,1H), 9.79 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=8.9 Hz, 1H),7.58-7.32 (m, 6H), 7.25-7.07 (m, 5H), 6.84-6.65 (m, 1H), 6.46 (d, J=15.4Hz, 1H), 5.88 (s, 2H), 4.02-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H).LC-MS (ESI): m/z (M+1) 522.

Example 2 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(9)

In a similar manner as described in Example 1,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(9) (29 mg, 28%) was prepared as a white solid from intermediate 7 (80mg, 0.19 mmol) and (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride.¹H NMR (400 MHz, DMSO) δ 10.58 (s, 1H), 9.64 (s, 1H), 8.11 (s, 1H), 8.02(s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.56-7.39 (m, 5H), 7.36 (d, J=8.9 Hz,1H), 7.23-7.11 (m, 5H), 6.85-6.73 (m, 1H), 6.49 (d, J=15.3 Hz, 1H), 5.90(s, 2H), 4.23-3.96 (m, 2H), 2.86 (s, 4H), 0.87 (d, J=30.2 Hz, 4H). LC-MS(ESI): m/z (M+1) 548.

Example 3 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)but-2-enamide(10)

In a similar manner as described in Example 1,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)but-2-enamide(10) (29 mg, 27%) was prepared as a white solid from intermediate 7 (80mg, 0.19 mmol) and (E)-4-(cyclobutyl(methyl)amino)but-2-enoyl chloride.¹H NMR (400 MHz, DMSO) δ 10.29 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.67(d, J=8.9 Hz, 1H), 7.58-7.38 (m, 5H), 7.30 (d, J=8.7 Hz, 1H), 7.24-7.09(m, 5H), 6.82-6.65 (m, 1H), 6.27 (d, J=14.8 Hz, 1H), 5.85 (s, 2H),3.14-2.93 (m, 2H), 2.92-2.75 (m, 1H), 2.02 (s, 3H), 1.99-1.90 (m, 2H),1.87-1.68 (m, 2H), 1.69-1.50 (m, 2H). LC-MS (ESI): m/z (M+1) 562.

Example 4 Synthesis ofN-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)acrylamide(11)

In a similar manner as described in Example 1,N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)acrylamide(11) (33 mg) was prepared as a off-white solid as a TFA salt afterprep-HPLC purification from intermediate 7 and acryloyl chloride. LC-MS(ESI): m/z (M+1) 449.

Example 5 Synthesis of(E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(14)

To a mixture of tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (300 mg, 0.88mmol) and 4 A MS (300 mg) in dry DMF (10 mL) were added4-chlorophenylboronic acid (413 mg, 2.64 mmol), Cu(OAc)₂ (160 mg, 0.88mmol) and pyridine (1 mL). The reaction mixture was heated to 35° C.overnight under an O₂ atmosphere, and filtered through a Celite pad. Thefiltrate was diluted with water (50 mL), extracted with EtOAc (30 mL×3).The combined organic layer was washed with water and brine, dried overNa₂SO₄, and concentrated. The residue was purified by columnchromatography (silica gel, 0 to 5% methanol in methylene chloride) togive tert-butyl3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate(12) (234 mg, 59.1%). LC-MS (ESI): m/z (M/M+2) 453/455.

To a solution of tert-butyl3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl) phenylcarbamate(12) (234 mg, 0.52 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise.The reaction mixture was stirred at rt for 1 h before concentrated. Theresidue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to give6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one as abrown solid (13) (180 mg, 98.9%). LC-MS (ESI): m/z (M/M+2) 353/355.

To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloridesalt (94 mg, 0.57 mmol) in dry acetonitrile (5 mL) was added 1 drop ofDMF before introducing (COCl)₂ (0.5 mL, 5.3 mmol). Resulting mixture wasstirred at room temperature for 1 hour. Concentrated and dissolved indry DCM (2 mL) before introducing a solution of6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one (13)(100 mg, 0.28 mmol) in DCM (2 mL). Resulting solution was stirred atroom temperature for 2 hours before quenched the reaction with MeOH (2mL). Solvent was removed and the residue was pre-purified by columnchromatography (silica gel, 0 to 10% methanol in methylene chloride(0.3% Et₃N)) followed by preparative HPLC (RP, C18, 10 to 95%acetonitrile in water (0.2% NH₃.H₂O)) to give(E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(14) (25 mg, 19.1%) as a white solid. LC-MS (ESI): m/z (M/M+2) 464/466.¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.82 (s, 1H), 8.11 (s, 1H), 7.99(s, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.7 Hz, 2H), 7.56-7.45 (m,3H), 7.35 (d, J=8.8 Hz, 1H), 6.82-6.65 (m, 1H), 6.46 (d, J=15.3 Hz, 1H),5.98 (s, 2H), 4.01-3.87 (m, 2H), 2.79 (s, 3H), 2.78 (s, 3H).

Example 6 Synthesis of(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(17)

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)but-2-enamide(17) (26 mg) was prepared as a white solid in three steps starting fromintermediate 5 and 3-methoxy-4-methylphenylboronic acid. LC-MS (ESI):m/z (M+1) 474. ¹H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 9.79 (s, 1H),8.11 (s, 1H), 8.00 (s, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.50 (t, J=8.1 Hz,1H), 7.39-7.29 (m, 2H), 7.15 (s, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.79-6.69(m, 1H), 6.46 (d, J=15.2 Hz, 1H), 5.74 (s, 2H), 3.97-3.90 (m, 2H), 3.80(s, 3H), 2.79 (s, 3H), 2.78 (s, 3H), 2.22 (s, 3H).

Example 7 Synthesis of(E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(27)

To a solution of 3-nitroaniline (10 g, 72.5 mmol), triethylamine (10 mL)and 4-(N, N-dimethylamino)pyridine (4.42 g, 36.3 mmol) in anhydrousCH₂Cl₂ (150 mL) was added a solution of di-tert-butyl dicarbonate (15.8g, 72.5 mmol) in CH₂Cl₂ (50 mL) dropwise. The mixture was stirred atroom temperature for 3 hours and washed with brine. The organic phasewas dried over Na₂SO₄, concentrated in vacuo and the residue waspurified by column chromatography (silica gel, 0 to 20% ethyl acetate inpetroleum ether) to give tert-butyl 3-nitrophenylcarbamate (18) 8.3 g asyellow solid (yield 48%). LC-MS (ESI): m/z (M+1) 237.

To a suspension of NaH (60% dispersion in mineral oil, 2.1 g, 41.8 mmol)in DMF (80 mL) at 0° C. was added a solution of tert-butyl3-nitrophenylcarbamate (18) (8.3 g, 34.9 mmol) in DMF (50 mL). Themixture was stirred at 0° C. for 0.5 hour before CH₃I (4.9 mL, 52.35mmol) was added dropwise. The reaction mixture was stirred at roomtemperature for 2 hours, diluted with water (200 mL), and extracted withDCM (60 mL×3). The combined organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo to afford tert-butylmethyl(3-nitrophenyl)carbamate (19) 8.8 g as yellow solid (yield 100%).LC-MS (ESI): m/z (M+1) 253.

A round-bottom flask containing tert-butylmethyl(3-nitrophenyl)carbamate (19) (8.8 g, 34.9 mmol), 10% palladium oncharcoal (880 mg), and THF-MeOH (80 mL/80 mL) was evacuated and flushedwith hydrogen three times. The mixture was stirred vigorously overnightunder an atmosphere of hydrogen. The catalyst was removed by filtrationthrough a pad of Celite, and the filtrate evaporated to affordtert-butyl 3-aminophenyl(methyl)carbamate (20) 7 g as yellow solid(yield 91%). LC-MS (ESI): m/z (M+1) 223.

To a solution of tert-butyl 3-aminophenyl(methyl)carbamate (20) (4.6 g,20.8 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7 g,19.8 mmol) in dioxane (100 mL) was added Et₃N (6 mL) and the reactionmixture was stirred at 60° C. overnight. The mixture was cooled to roomtemperature, the solvent was evaporated before water (200 mL) and EA(100 mL) was introduced. Organic layer was separated and extracted withEA (60 mL×2). After the organic layer was washed with brine and driedover anhydrous sodium sulfate, the solvent was evaporated. The residuewas purified by column chromatography (silica gel, 0 to 30% ethylacetate in petroleum ether) to give tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl (methyl)carbamate(21) 6.7 g as yellow solid (yield 63%). LC-MS (ESI): m/z (M+1) 541.

To a solution of tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl (methyl)carbamate(21) (6.7 g, 12.4 mmol) in THF/MeOH/H₂O (100 mL/50 mL/30 mL) was addedFe powder (3.47 g, 62 mmol) and NH₄Cl (6.63 g, 124 mmol). The reactionmixture was heated at 50° C. for 5 h under N₂. After cooling to rt, thereaction mixture was filtered through a pad of Celite. The filtrate wasextracted with EtOAc (30 mL×3), washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo to afford tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate(22) (6 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.

To a stirred solution of tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate(22) (3.1 g, 6.08 mmol) and TEA (1.75 mL, 12.16 mmol) in dry DCM (40 mL)at 0° C. and under N₂ atmosphere was added a solution of triphosgene(722 mg, 2.43 mmol) in dry DCM (20 mL) dropwise during 1 h. After thestirring was continued for 1 h, the reaction was quenched with water (10mL). The organic layer was separated, washed with water and brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, 0 to 20% ethyl acetate in petroleumether) to give tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(23) (3 g, 92%) as a light brown solid. LC-MS (ESI): m/z (M+1) 537.

To a mixture of tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate(23) (3 g, 5.6 mmol) in MeOH (120 mL) was added Pd(OH)₂/C (3 g, 20 wt %)and 6 drops of con. HCl. The resulting mixture was purged with H₂ (2×)before heated to 60° C. overnight under H₂ atmosphere. The mixture wascooled to r.t., filtered through a Celite pad, and the solvent wasremoved in vacuo to give tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (1.9 g,95%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 357.

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(27) (55 mg) was prepared as a white solid in three steps fromtert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(24). LC-MS (ESI): m/z (M/M+2) 478/480. ¹H NMR (400 MHz, DMSO) δ 8.12(s, 1H), 7.71-7.52 (m, 5H), 7.48 (d, J=8.7 Hz, 2H), 7.34 (d, J=7.8 Hz,1H), 6.65 (dt, J=15.2, 6.0 Hz, 1H), 6.11-5.90 (m, 3H), 3.27 (s, 3H),2.91 (d, J=5.7 Hz, 2H), 2.04 (s, 6H).

Example 8 Synthesis of(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(30)

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(30) (26 mg) was prepared as a white solid in three steps starting fromintermediate 24 and 3-methoxy-4-methylphenylboronic acid. LC-MS (ESI):m/z (M+1) 488. ¹H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.71-7.55 (m, 3H),7.33 (t, J=8.1 Hz, 2H), 7.12 (s, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.71-6.59(m, 1H), 6.03 (m, 1H), 5.74 (br, 2H), 3.80 (s, 3H), 3.27 (s, 3H), 2.91(d, J=5.7 Hz, 2H), 2.21 (s, 3H), 2.04 (s, 6H).

Example 9 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(33)

To a mixture of tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate (24) (600mg, 1.68 mmol) and 4 A MS (800 g) in dry DMF (10 mL) were added TFA4-phenoxyphenylboronic acid (1.08 g, 5.06 mmol), Cu(OAc)₂ (307 mg, 1.68mmol) and pyridine (1 mL). The reaction mixture was heated to 37° C.overnight under O₂ atmosphere, and filtered through a Celite pad. Thefiltrate was diluted with water (30 mL), extracted with EtOAc (10 mL×3).The combined organic layer was washed with water and brine, dried overNa₂SO₄, and concentrated. The residue was purified by columnchromatography (silica gel, 0 to 510% methanol in methylene chloride(0.3% methanol in methylene chloride) to give tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamateas a light yellow solid (31) (450 mg, 51%). LC-MS (ESI): m/z (M+1) 525.

To a solution of tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (31) (450 mg, 0.86 mmol) in DCM (8 mL) was addedTFA (2 mL) dropwise. The reaction mixture was stirred at rt for 1 h andthen concentrated. The residue was purified by column chromatography(silica gel, to 1064 methanol in methylene chloride (0.3% Et₃N)) to give6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (364 mg, 100%). LC-MS (ESI): m/z (M+1) 425.

To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloridesalt (95 mg, 0.57 mmol) in acetonitrile (5 mL) was added 1 drop of DMFbefore introducing (COCl)₂ (0.25 mL, 2.86 mmol). Resulting mixture wasstirred at room temperature for 2 hours. Concentrated and dissolved inDCM (2 mL) before introduced to the solution of6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (100 mg, 0.24 mmol) in DCM (2 mL). Resulting solution was stirredat room temperature for 2 hours before quenched the reaction with MeOH(2 mL). Solvent was removed and the residue was pre-purified by columnchromatography (silica gel, 0 to 10% methanol in methylene chloride (1%Et₃N)) followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile inwater (0.2% NH₃)) to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(33) (60 mg, 47%) as white solid. LC-MS (ESI): m/z (M+1) 536. ¹H NMR(400 MHz, DMSO) δ 8.11 (s, 1H), 7.72-7.56 (m, 3H), 7.51-7.33 (m, 5H),7.23-7.09 (m, 5H), 6.65 (dt, J=15.2, 6.1 Hz, 1H), 6.04 (d, J=16.6 Hz,1H), 5.90 (br, 2H), 3.27 (s, 3H), 2.99 (s, 2H), 2.10 (s, 6H).

Example 10 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(34)

In a similar manner as described in Example 9,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(34) (67 mg) was prepared as a white solid from intermediate 32 and(E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M+1) 562. ¹H NMR (400 MHz, DMSO) δ 8.11 (s, 1H), 7.70-7.56 (m, 3H),7.52-7.30 (m, 5H), 7.23-7.10 (m, 5H), 6.72-6.62 (m, 1H), 5.99 (d, J=14.3Hz, 1H), 5.90 (s, 2H), 3.27 (s, 3H), 3.11 (d, J=6.4 Hz, 2H), 2.11 (s,3H), 1.64-1.54 (m, 1H), 0.39-0.28 (m, 2H), 0.25-0.11 (m, 2H).

Example 11 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(35)

In a similar manner as described in Example 9,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(35) (61 mg) was prepared as a white solid from intermediate 32 and(E)-4-(cyclobutyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M+1) 576. ¹H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.71-7.57 (m, 3H),7.50-7.36 (m, 5H), 7.21-7.11 (m, 5H), 6.74-6.61 (m, 1H), 6.29-6.00 (m,1H), 5.91 (s, 2H), 3.50-3.30 (m, 4H), 2.35-1.74 (m, 7H), 1.63-1.44 (m,2H).

Example 12 Synthesis of(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(43)

To a solution of N-methyl-4-nitroaniline (5.0 g, 32.9 mmol) in THF (50mL) were added di-tert-butyl dicarbonate (10.76 g, 49.4 mmol) and DMAP(201 mg, 1.6 mmol). The reaction mixture was refluxed under N₂ for 2 hbefore cooled to rt. After removal of the solvent, the residue wasdissolved with EtOAc (200 mL). The resulting solution was washed withwater and brine, dried over Na₂SO₄, and concentrated in vacuo to givetert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 100%) as a brown oil.To a solution of tert-butyl methyl(4-nitrophenyl)carbamate (8.3 g, 32.9mmol) in THF/MeOH/H₂O (150 mL/40 mL/80 mL) was added Fe powder (9.4 g,168 mmol) and NH₄Cl (18 g, 337 mmol). The reaction mixture was heated at50° C. for 4 h under N₂. After cooling to rt, the reaction mixture wasfiltered through a pad of Celite. The filtrate was extracted with EtOAc(100 mL×3), washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo to afford tert-butyl4-aminophenyl(methyl)carbamate (36) (7.3 g, yield 100%) as a yellowsolid. LC-MS (ESI): m/z (M+1) 223.

To a solution of tert-butyl 4-aminophenyl(methyl)carbamate (36) (7 g,31.5 mmol) and N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (11.2g, 31.5 mmol) in dioxane (100 mL) was added Et₃N (8 mL) and the reactionmixture was stirred at 60° C. overnight. The mixture was cooled to roomtemperature, the solvent was evaporated before water (200 mL) and EA(100 mL) was introduced. The organic layer was separated and extractedwith EA (60 mL×2). After the organic layer was washed with brine anddried over anhydrous sodium sulfate, the solvent was evaporated. Theresidue was purified by column chromatography (silica gel, 0 to 30%ethyl acetate in petroleum ether) to give tert-butyl4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino) phenyl(methyl)carbamate(37) 9 g as yellow solid (yield 53%). LC-MS (ESI): m/z (M+1) 541.

To a solution of tert-butyl4-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)phenyl (methyl)carbamate(37) (6 g, 11.1 mmol) in THF/MeOH/H₂O (100 mL/100 mL/30 mL) was added Fepowder (3.11 g, 55.5 mmol) and NH₄Cl (5.94 g, 111 mmol). The reactionmixture was heated at 60° C. for 4 h under N₂. After cooling to rt, thereaction mixture was filtered through a pad of Celite. The filtrate wasextracted with EtOAc (100 mL×3), washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo to afford tert-butyl4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate(38) (5.4 g, yield 95%) as a yellow solid. LC-MS (ESI): m/z (M+1) 511.

To a stirred solution of tert-butyl4-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)phenyl(methyl)carbamate(38) (5.4 g, 10.6 mmol) and TEA (2.14 g, 21.2 mmol) in dry DCM (60 mL)at 0° C. and under N₂ atmosphere, was added a solution of triphosgene(1.07 g, 3.6 mmol) in dry DCM (30 mL) dropwise during 1 h. Stirring wascontinued for 1 h before the reaction was quenched with water (20 mL).The organic layer was separated, washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether)to give tert-butyl4-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(39) (4.2 g, 74%) as a light brown solid. LC-MS (ESI): m/z (M+1) 537.

To a mixture of tert-butyl4-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate(39) (3 g, 5.6 mmol) in MeOH (120 mL) was added Pd(OH)₂/C (3 g, 20 wt %)and 6 drops of con. HCl. The resulting mixture was purged with H₂ (2×)and heated to 60° C. overnight under H₂ atmosphere. The mixture wascooled to r.t., filtered through a Celite pad, and the solvent wasremoved in vacuo to obtain tert-butyl4-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (40) (2 g,100%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 357.

In a similar manner as described in Example 9,(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(43) (25 mg) was prepared as a white solid in three steps starting fromintermediate 40. LC-MS (ESI): m/z (M+1) 536. ¹H NMR (400 MHz, DMSO) δ9.69 (s, 1H), 8.13 (s, 1H), 7.76 (d, J=8.4 Hz, 2H), 7.59-7.37 (m, 6H),7.29-7.05 (m, 5H), 6.77-6.57 (m, 1H), 6.36-6.11 (m, 1H), 5.92 (s, 2H),3.91-3.69 (m, 2H), 3.31 (s, 3H), 2.68 (s, 6H).

Example 13 Synthesis of(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(44)

In a similar manner as described in Example 12,(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(44) (27 mg) was prepared as a white solid from intermediate 42 and(E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M+1) 562. ¹H NMR (400 MHz, DMSO) δ 9.51 (s, 1H), 8.13 (s, 1H), 7.76 (d,J=8.5 Hz, 2H), 7.56-7.39 (m, 6H), 7.26-7.10 (m, 5H), 6.79-6.62 (m, 1H),6.34-6.13 (m, 1H), 5.94 (s, 2H), 4.12-3.82 (m, 2H), 3.31 (s, 3H), 2.76(s, 4H), 0.97-0.67 (m, 4H).

Example 14 Synthesis of(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(45)

In a similar manner as described in Example 11,(E)-N-(4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(45) (61 mg) was prepared as a white solid from intermediate 42 and(E)-4-(cyclobutyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M+1) 576. ¹H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 8.13 (s, 1H), 7.76 (d,J=8.4 Hz, 2H), 7.56-7.38 (m, 6H), 7.26-7.09 (m, 5H), 6.74-6.57 (m, 1H),6.34-6.15 (m, 1H), 5.93 (s, 2H), 3.89-3.76 (m, 1H), 3.72-3.50 (m, 2H),3.30 (s, 3H), 2.53 (d, J=4.4 Hz, 3H), 2.20-2.00 (m, 4H), 1.76-1.55 (m,2H).

Example 15 Synthesis of(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(48)

In a similar manner as described in Example 12,(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(48) (34 mg) was prepared as a white solid in three steps starting fromintermediate 40 and 4-chlorophenylboronic acid. LC-MS (ESI): m/z (M/M+2)479/481. ¹H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.73 (d, J=8.6 Hz, 2H),7.63 (d, J=8.7 Hz, 2H), 7.48 (dd, J=19.3, 8.7 Hz, 4H), 6.72-6.60 (m,1H), 6.08-5.90 (m, 3H), 3.27 (s, 3H), 2.95 (d, J=5.2 Hz, 2H), 2.08 (s,6H).

Example 16 Synthesis of(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(49)

In a similar manner as described in Example 15,(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(49) (32 mg) was prepared as a white solid from intermediate 47 and(E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M/M+2) 504/506. ¹H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.72 (d, J=8.7Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.47 (dd, J=23.1, 8.7 Hz, 4H),6.76-6.61 (m, 1H), 6.09-5.83 (m, 3H), 3.27 (s, 3H), 3.11 (d, J=5.9 Hz,2H), 2.13 (s, 3H), 1.68-1.55 (m, 1H), 0.42-0.29 (m, 2H), 0.26-0.17 (m,2H).

Example 17 Synthesis of(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(50)

In a similar manner as described in Example 15,(E)-N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclobutyl(methyl)amino)-N-methylbut-2-enamide(50) (30 mg) was prepared as a white solid from intermediate 47 and(E)-4-(cyclobutyl(methyl)amino)but-2-enoyl chloride. LC-MS (ESI): m/z(M/M+2) 518/520. ¹H NMR (400 MHz, DMSO) δ 9.84 (s, 1H), 8.13 (s, 1H),7.75 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.49 (d, J=7.1 Hz, 4H),6.74-6.57 (m, 1H), 6.36-6.15 (m, 1H), 6.03 (s, 2H), 3.90-3.74 (m, 1H),3.72-3.51 (m, 2H), 3.30 (s, 3H), 2.53 (d, J=4.4 Hz, 3H), 2.21-2.00 (m,4H), 1.82-1.53 (m, 2H).

Example 18 Synthesis ofN-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(51)

In a similar manner as described in Example 15,N-(4-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(51) (40 mg) was prepared as a white solid from intermediate 47 andacryloyl chloride. LC-MS (ESI): m/z (M/M+2) 421/423. ¹H NMR (400 MHz,DMSO) δ 8.13 (s, 1H), 7.72 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H),7.48 (dd, J=17.1, 8.5 Hz, 4H), 6.24-6.07 (m, 2H), 5.99 (s, 2H),5.67-5.57 (m, 1H), 3.29 (s, 3H).

Example 19 Synthesis of(E)-N-(4-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(54)

In a similar manner as described in Example 12,(E)-N-(4-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(54) (45 mg) was prepared as a white solid in three steps starting fromintermediate 40 and 3-methoxy-4-methylphenylboronic acid. LC-MS (ESI):m/z (M+1) 488. ¹H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.13 (s, 1H), 7.76(d, J=8.5 Hz, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.33 (d, J=7.8 Hz, 1H),7.16-7.09 (m, 1H), 7.06-6.97 (m, 1H), 6.75-6.57 (m, 1H), 6.30-6.14 (m,1H), 5.78 (s, 2H), 3.80 (s, 5H), 3.30 (s, 3H), 2.69 (s, 3H), 2.68 (s,3H), 2.22 (s, 3H).

Example 20 Synthesis ofN-(4-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(55)

In a similar manner as described in Example 19,N-(4-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(55) (30 mg) was prepared as a white solid from intermediate 53 andacryloyl chloride. LC-MS (ESI): m/z (M+1) 431. ¹H NMR (400 MHz, DMSO) δ8.12 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.7 Hz, 2H), 7.33 (d,J=7.7 Hz, 1H), 7.14 (s, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.23-6.05 (m, 2H),5.73 (s, 2H), 5.66-5.58 (m, J=12.0 Hz, 1H), 3.80 (s, 3H), 3.29 (d, J=8.0Hz, 3H), 2.22 (s, 3H).

Example 21 Synthesis of(R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(63)

In a similar manner as described in Example 1,(R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(62) (174 mg) was prepared as a brown oil starting from (R)-tert-butyl3-aminopyrrolidine-1-carboxylate (56). LC-MS (ESI): m/z (M+1) 389. ¹HNMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.46 (d,J=8.7 Hz, 2H), 7.33 (d, J=7.7 Hz, 1H), 7.14 (s, 1H), 7.02 (d, J=7.8 Hz,1H), 6.23-6.05 (m, 2H), 5.73 (s, 2H), 5.66-5.58 (m, J=12.0 Hz, 1H), 3.80(s, 3H), 3.29 (d, J=8.0 Hz, 3H), 2.22 (s, 3H).

A solution of(R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(62) (95 mg, 0.24 mmol), 4-(cyclopropyl(methyl)amino)but-2-enoic acidhydrochloride (69 mg, 0.36 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mLdry DMF was cooled to 0° C. HBTU (190 mg, 0.49 mmol) was added in oneportion. The reaction mixture was allowed to warm to rt, and stirred for2 hrs under N₂, then purified directly by Gilson using 10 to 95%acetonitrile in water (0.2% NH₃.H₂O) to give(R,E)-6-amino-9-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(63) (31 mg, 17.7%) as a light yellow solid. LC-MS (ESI): m/z (M+1) 526.¹H NMR (400 MHz, DMSO) δ 8.14 (d, J=6.0 Hz, 1H), 7.55-7.34 (m, 4H),7.30-7.08 (m, 5H), 6.76-6.59 (m, 1H), 6.36 (dd, J=37.4, 15.1 Hz, 1H),5.82 (d, J=9.1 Hz, 2H), 5.20-4.99 (m, 1H), 4.11-3.40 (m, 4H), 3.26 (dd,J=17.7, 6.4 Hz, 2H), 2.78-2.59 (m, 1H), 2.24 (d, J=12.4 Hz, 3H),1.80-1.63 (m, 1H), 0.51-0.37 (m, 2H), 0.37-0.24 (m, 2H).

Example 22 Synthesis of(R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(64)

A mixture of(R)-6-amino-7-(4-phenoxyphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(62) (95 mg, 0.24 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acidhydrochloride (76 mg, 0.37 mmol) and DIPEA (213 μL, 1.2 mmol) in 5 mLdry DMF was cooled to 0° C., HBTU (190 mg, 0.49 mmol) was added in oneportion. The reaction mixture was allowed to warm up to rt, and stirredfor 2 hrs under N₂, and purified directly by preparative-HPLC (RP C18,10 to 95% acetonitrile in water (0.2% NH₃.H₂O)) to give(R,E)-6-amino-9-(1-(4-(cyclobutyl(methyl)amino)but-2-enoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (64) (36 mg,25.9%) as a light yellow solid. LC-MS (ESI): m/z (M/M+2) 518/520. ¹H NMR(400 MHz, DMSO) δ 8.11 (d, J=6.0 Hz, 1H), 7.48-7.36 (m, 4H), 7.23-7.07(m, 5H), 6.69-6.55 (m, 1H), 6.34 (dd, J=35.9, 15.1 Hz, 1H), 5.89-5.67(m, 2H), 5.18-4.95 (m, 1H), 4.15-3.42 (m, 4H), 2.97 (dd, J=18.6, 6.2 Hz,2H), 2.85-2.73 (m, 1H), 2.73-2.58 (m, 1H), 2.33-2.10 (m, 1H), 1.98 (d,J=12.6 Hz, 3H), 1.95-1.87 (m, 2H), 1.80-1.67 (m, 2H), 1.63-1.48 (m, 2H).

Example 23 Synthesis of(R,E)-6-amino-7-(4-chlorophenyl)-9-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-7H-purin-8(9H)-one(67)

In a similar manner as described in Example 21,(R,E)-6-amino-7-(4-chlorophenyl)-9-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-7H-purin-8(9H)-one(67) (24 mg) was prepared as a white solid in three steps starting fromintermediate 60 and 4-chlorophenylboronic acid. LC-MS (ESI): m/z (M+1)442. ¹H NMR (400 MHz, DMSO) δ 8.12 (d, J=5.9 Hz, 1H), 7.65-7.53 (m, 2H),7.41 (dd, J=8.7, 3.3 Hz, 2H), 6.70-6.54 (m, 1H), 6.39 (dd, J=38.2, 15.2Hz, 1H), 5.89 (d, J=11.1 Hz, 2H), 5.19-4.97 (m, 1H), 4.12-3.57 (m, 3H),3.12 (dd, J=19.6, 5.8 Hz, 2H), 2.76-2.55 (m, J=21.1, 10.8 Hz, 1H), 2.22(s, 3H), 2.19 (s, 3H).

Example 24 Synthesis of(E)-6-amino-9-((1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)methyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(75)

In a similar manner as described in Example 21,(E)-6-amino-9-((1-(4-(dimethylamino)but-2-enoyl)piperidin-4-yl)methyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(75) (31 mg) was prepared as a white solid starting from tert-butyl4-(aminomethyl)piperidine-1-carboxylate 68. LC-MS (ESI): m/z (M+1) 528.¹H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.49-7.36 (m, 4H), 7.25-7.06 (m,5H), 6.60-6.50 (m, 2H), 5.78 (s, 2H), 4.35 (d, 1H), 3.98 (d, 1H), 3.72(d, J=7.2 Hz, 2H), 3.05-2.92 (m, 3H), 2.65-2.52 (m, 1H), 2.11 (s, 6H),1.63 (s, 2H), 1.22-0.94 (m, 3H).

Example 25 Synthesis ofN-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(76)

A solution of6-amino-7-(3-methoxy-4-methylphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(29) (80 mg, 0.21 mmol) in anhydrous DCM (5 mL) was added acryloylchloride (26 μL, 0.32 mmol) at 0° C. The reaction mixture was stirredfor 1 hr under N₂ before it was quenched with MeOH. The solvents wereremoved, and the residue was purified by preparative HPLC (RP C18, 10 to95% acetonitrile in water (0.2% NH₃.H₂O)) to giveN-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(76) (30 mg, 33%) as a white solid. LC-MS (ESI): m/z (M+1) 431.2. ¹H NMR(400 MHz, DMSO) δ 8.12 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.66-7.54 (m,2H), 7.39-7.25 (m, 2H), 7.13 (d, J=1.8 Hz, 1H), 6.28-6.07 (m, 2H), 5.71(s, 2H), 5.64-5.57 (m, 1H), 3.80 (s, 3H), 3.29 (s, 3H), 2.22 (s, 3H).

Example 26 Synthesis ofN-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(77)

In a similar manner as described in Example 25,N-(3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methylacrylamide(77) (40 mg, 44%) was prepared as a white solid starting from6-amino-7-(4-chlorophenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(26) (80 mg). LC-MS (ESI): m/z (M+1) 421.1. ¹H NMR (400 MHz, DMSO) δ8.13 (s, 1H), 7.77-7.54 (m, 5H), 7.53-7.22 (m, 3H), 6.18 (s, 2H), 5.95(s, 2H), 5.72-5.42 (m, 1H), 3.28 (s, 3H).

Example 27 Synthesis of(R)-9-(1-acryloylpyrrolidin-3-yl)-6-amino-7-(4-chlorophenyl)-7H-purin-8(9H)-one(78)

In a similar manner as described in Example 25,(R)-9-(1-acryloylpyrrolidin-3-yl)-6-amino-7-(4-chlorophenyl)-7H-purin-8(9H)-one(78) (55 mg, 40%) was prepared as a white solid starting from(R)-6-amino-7-(4-chlorophenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(66) (119 mg). LC-MS (ESI): m/z (M+1) 385.1. ¹H NMR (400 MHz, DMSO) δ8.15 (d, J=2.8 Hz, 1H), 7.58 (d, J=8.6 Hz, 2H), 7.42 (dd, J=8.8, 2.6 Hz,2H), 6.69-6.44 (m, 1H), 6.14 (dt, J=16.7, 2.3 Hz, 1H), 5.94 (s, 2H),5.71-5.60 (m, 1H), 5.21-4.98 (m, 1H), 4.16-3.34 (m, 4H), 2.76-2.54 (m,1H), 2.35-2.11 (m, 1H).

Example 28 Synthesis of(R,E)-6-amino-9-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(81)

To a mixture of (R)-tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate (60) (75mg, 0.23 mmol) and 4 A MS (200 mg) in dry DMF (5 mL) were added2-methoxy-1-methyl-4-phenoxybenzene (150 mg, 0.9 mmol), Cu(OAc)₂ (43 mg,0.23 mmol) and pyridine (111 μL, 1.4 mmol). The resulting mixture washeated to 35° C. overnight under O₂ atmosphere. After cooled down to rt,the reaction solution was filtered through a Celite pad. The filtratewas diluted with water (50 mL) and extracted with EtOAc (30 mL×3). Thecombined organic layers were washed with water and brine, dried overNa₂SO₄, and concentrated. The residue was purified by columnchromatography (silica gel, 0 to 5% methanol in methylene chloride) togive (R)-tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate(79) (93 mg, 90%) as a brown oil. LC-MS (ESI): m/z (M+1) 441.

To a solution of (R)-tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)pyrrolidine-1-carboxylate(79) (93 mg, 0.21 mmol) in DCM (3 mL) was added TFA (0.8 mL) dropwise.The reaction mixture was stirred at rt for 1 hr before concentrated invacuo to give(R)-6-amino-7-(3-methoxy-4-methylphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(80) (72 mg, 100%) as a brown solid. LC-MS (ESI): m/z (M+1) 341.

A mixture of(R)-6-amino-7-(3-methoxy-4-methylphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(80) (72 mg, 0.21 mmol), (E)-4-(dimethylamino)but-2-enoic acidhydrochloride (42 mg, 0.25 mmol) and DIPEA (187 μL, 1.1 mmol) in dry DMF(5 mL) was cooled down to 0° C. HBTU (164 mg, 0.42 mmol) was added inone portion. The reaction mixture was allowed to warm up to rt, andstirred for 2 hrs under N₂. The reaction solution was directly loaded toa prep HPLC and purified by using 10 to 95% acetonitrile in water (0.2%NH₃.H₂O) to give(R,E)-6-amino-9-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(81) (49 mg, 51%) as a white solid. LC-MS (ESI): m/z (M+1) 452. ¹H NMR(400 MHz, DMSO) δ 8.13 (d, J=5.9 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.06(dd, J=5.2, 1.8 Hz, 1H), 7.00-6.91 (m, 1H), 6.70-6.59 (m, 1H), 6.39 (dd,J=35.5, 15.2 Hz, 1H), 5.65 (s, 2H), 5.21-5.00 (m, 1H), 4.12-3.86 (m,2H), 3.81 (s, 3H), 3.79-3.39 (m, 2H), 3.04 (dd, J=16.6, 5.6 Hz, 2H),2.81-2.59 (m, 1H), 2.22 (s, 3H), 2.17 (s, 3H), 2.14 (s, 3H).

Example 29 Synthesis of(R)-9-(1-acryloylpyrrolidin-3-yl)-6-amino-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(82)

In a similar manner as described in Example 25,(R)-9-(1-acryloylpyrrolidin-3-yl)-6-amino-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(82) (27 mg, 25%) was prepared as a white solid starting from(R)-6-amino-7-(3-methoxy-4-methylphenyl)-9-(pyrrolidin-3-yl)-7H-purin-8(9H)-one(80) (93 mg). LC-MS (ESI): m/z (M+1) 395.2. ¹H NMR (400 MHz, DMSO) δ8.11 (d, J=5.3 Hz, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.04 (dd, J=4.8, 1.9 Hz,1H), 6.98-6.86 (m, 1H), 6.68-6.45 (m, 1H), 6.14 (dd, J=16.9, 2.0 Hz,1H), 5.76-5.51 (m, 3H), 5.22-4.93 (m, 1H), 4.12-3.87 (m, 2H), 3.83-3.72(m, 4H), 3.70-3.37 (m, 1H), 2.79-2.56 (m, 1H), 2.35-2.11 (m, 4H).

Example 30 Synthesis of(R)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(4-chlorophenyl)-7H-purin-8(9H)-one(90)

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (83)(600 mg, 3.0 mmol) and TEA (0.85 mL, 6.1 mmol) in dioxane (20 mL) wasadded N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (1.28 g, 3.6mmol). The reaction mixture was heated to 70° C. for 6 h under N₂ beforewater (20 mL) was introduced. The resulting mixture was cooled to rt andextracted with EtOAc (30 mL×3). The combined organic layer was washedwith brine, dried over Na₂SO₄, and concentrated in vacuo. The residuewas purified by column chromatography (silica gel, 0 to 15% ethylacetate in petroleum ether) to give (R)-tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)piperidine-1-carboxylate (84) (0.8 g, 51.5%) as a yellow solid. LC-MS(ESI): m/z (M+1) 519.

To a solution of (R)-tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)piperidine-1-carboxylate (84) (0.8 g, 1.5 mmol) in THF/MeOH/H₂O (20mL/10 mL/5 mL) were added Fe powder (0.43 g, 7.7 mmol) and NH₄Cl (0.83g, 15.4 mmol). The reaction mixture was heated to 50° C. for 7 h underN₂. After cooling to rt, the reaction mixture was filtered through a padof Celite. The filtrate was extracted with EtOAc (30 mL×3), washed withwater and brine, dried over Na₂SO₄, and concentrated in vacuo to afford(R)-tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)piperidine-1-carboxylate(85) (750 mg, 99.5%) as a brown solid. LC-MS (ESI): m/z (M+1) 489.

To a stirred solution of (R)-tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)piperidine-1-carboxylate(85) (750 mg, 1.5 mmol) and TEA (430 μL, 3.1 mmol) in dry DCM (15 mL) at0° C. and under N₂ atmosphere, was added a solution of triphosgene (229mg, 0.77 mmol) in dry DCM (5 mL) dropwise during 1 h. After the stirringwas continued for 1 h, the reaction was quenched with water (30 mL). Theorganic layer was separated, washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether)to give (R)-tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(86) (668 mg, 84.6%) as a light brown solid. LC-MS (ESI): m/z (M+1) 515.

To a mixture of (R)-tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(86) (668 mg, 1.3 mmol) in MeOH (20 mL) was added Pd(OH)₂/C (660 mg, 20wt %) and 3 drops of con. HCl. The resulting mixture was purged with H₂(2×) before heated to 60° C. overnight under H₂ atmosphere. The mixturewas cooled to r.t., filtered through a Celite pad, and the solvent wasremoved in vacuo to obtain (R)-tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate (87) (434mg, 100%) as a white solid. LC-MS (ESI): m/z (M+1) 335.

In a similar manner as described in Example 23, (R)-tert-butyl3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(88) (173 mg, 100%) was prepared as a brown solid starting from(R)-tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate (87) (130mg) and 4-chlorophenylboronic acid (184 mg). LC-MS (ESI): m/z (M+1)445.3.

In a similar manner as described in Example 23,(R)-6-amino-7-(4-chlorophenyl)-9-(piperidin-3-yl)-7H-purin-8(9H)-one(89) (134 mg, 100%) was prepared as a brown oil starting from(R)-tert-butyl3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(88) (173 mg). LC-MS (ESI): m/z (M+1) 345.1.

In a similar manner as described in Example 23,(R)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(4-chlorophenyl)-7H-purin-8(9H)-one(90) (26 mg, 17%) was prepared as a white solid starting from(R)-6-amino-7-(4-chlorophenyl)-9-(piperidin-3-yl)-7H-purin-8(9H)-one(89) (134 mg). LC-MS (ESI): m/z (M/M+2) 399.2/401.2. ¹H NMR (400 MHz,DMSO) δ 8.13 (s, 1H), 7.63-7.53 (m, 2H), 7.43 (d, J=7.8 Hz, 2H),6.87-6.68 (m, 1H), 6.11 (dd, J=16.7, 2.2 Hz, 1H), 5.83 (s, 2H),5.72-5.59 (m, 1H), 4.58-4.03 (m, 3H), 3.93-2.92 (m, 1H), 2.66-2.49 (m,2H), 1.96-1.79 (m, 2H), 1.56-1.42 (m, 1H).

Example 31 Synthesis of(R)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(93)

In a similar manner as described in Example 28, (R)-tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(91) (57 mg, 32%) was prepared as a brown solid starting from(R)-tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate (87) (130mg) and 3-methoxy-4-methylphenylboronic acid (192 mg). LC-MS (ESI): m/z(M+1) 395.2. LC-MS (ESI): m/z (M+1) 455.2.

In a similar manner as described in Example 28,(R)-6-amino-7-(3-methoxy-4-methylphenyl)-9-(piperidin-3-yl)-7H-purin-8(9H)-one(92) (44 mg, 100%) was prepared as a brown oil starting from(R)-tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate(91) (57 mg). LC-MS (ESI): m/z (M+1) 345.1.

In a similar manner as described in Example 28,(R)-9-(1-acryloylpiperidin-3-yl)-6-amino-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(93) (30 mg, 61%) was prepared as a white solid starting from(R)-6-amino-7-(3-methoxy-4-methylphenyl)-9-(piperidin-3-yl)-7H-purin-8(9H)-one(92) (44 mg). LC-MS (ESI): m/z (M+1) 409.3. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.33-7.24 (m, 1H), 7.10-6.99 (m, 1H), 6.98-6.88 (m, 1H),6.88-6.69 (m, 1H), 6.12 (d, J=16.6 Hz, 1H), 5.73-5.51 (m, 3H), 4.58-3.70(m, 6H), 3.48-2.96 (m, 1H), 2.67-2.51 (m, 1H), 2.46-2.27 (m, 1H), 2.20(s, 3H), 1.97-1.77 (m, 2H), 1.60-1.36 (m, 1H).

Example 32 Synthesis of(E)-N-(5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(104)

To a solution of 2-amino-4-nitrophenol (8.0 g, 52 mmol) in EtOH (100 mL)was added Boc anhydride (22 g, 101 mmol). The reaction mixture wasstirred at rt for 24 h under N₂ atmosphere before the solvents wereremoved in vacuo. The residue was washed with petroleum ether, driedunder vacuum to give tert-butyl 2-hydroxy-5-nitrophenylcarbamate (94)(11.2 g, 85%) as a yellow solid. LC-MS (ESI): m/z (M−1) 253.1.

To a mixture of tert-butyl 2-hydroxy-5-nitrophenylcarbamate (94) (4.0 g,15.7 mmol) and K₂CO₃ (10.9 g, 79 mmol) in dry DMF (40 mL) was added1-bromo-2-methoxyethane (4.4 mL, 47 mmol) dropwise under N₂. Theresulting mixture was heated at 40° C. overnight, then filtered througha Celite pad. The filtrate was diluted with water (100 mL), extractedwith EtOAc (50 mL×3). The combined organic layer was washed with waterand brine, dried over Na₂SO₄, and concentrated. The residue was purifiedby column chromatography (silica gel, 0 to 30% ethyl acetate inpetroleum ether) to give tert-butyl2-(2-methoxyethoxy)-5-nitrophenylcarbamate (95) (3.5 g, 76%) as a brownoil. LC-MS (ESI): m/z (M+1) 311.2.

To a suspension of NaH (60% dispersion in mineral oil, 327 mg, 8.2 mmol)in anhydrous THF (15 mL) at 0° C. was added a solution of tert-butyl2-(2-methoxyethoxy)-5-nitrophenylcarbamate (95) (1.7 g, 5.4 mmol) in THF(10 mL). The mixture was stirred at 0° C. for 0.5 hour before CH₃I (0.5mL, 8.1 mmol) was introduced dropwise. The stirring was continued atr.t. overnight before concentrated down under reduced pressure. Theresidue was diluted with water (100 mL), extracted with EtOAc (50 mL×3).The combined organic layer was washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo to afford tert-butyl2-(2-methoxyethoxy)-5-nitrophenyl(methyl)carbamate (96) (1.8 g, quant.)as a brown solid. LC-MS (ESI): m/z (M+1) 327.2.

To a solution of tert-butyl2-(2-methoxyethoxy)-5-nitrophenyl(methyl)carbamate (96) (1.8 g, 5.5mmol) in THF/EtOH/H₂O (16 mL/8 mL/4 mL) were added iron powder (1.52 g,27 mmol) and NH₄Cl (2.94 g, 55 mmol). The resulting mixture was heatedat 50° C. for 7 hrs under N₂. After cooled down to r.t., the reactionmixture was filtered through a pad of Celite. The filtrate was extractedwith EtOAc (50 mL×3), washed with water and brine, dried over Na₂SO₄,and concentrated in vacuo to afford tert-butyl5-amino-2-(2-methoxyethoxy)phenyl(methyl)carbamate (97) (1.6 g, 99%) asa brown solid. LC-MS (ESI): m/z (M+1) 297.1.

To a solution of tert-butyl5-amino-2-(2-methoxyethoxy)phenyl(methyl)carbamate (97) (1.6 g, 5.4mmol) and TEA (1.5 mL, 10.8 mmol) in dioxane (50 mL) was addedN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (1.9 g, 5.4 mmol).The reaction mixture was heated at 70° C. overnight under N₂, beforewater (100 mL) was introduced. The resulting mixture was extracted withEtOAc (50 mL×3). The combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, 0 to 20% ethyl acetate in petroleumether) to give tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(98) (3.3 g, 98%) as a brown oil. LC-MS (ESI): m/z (M+1) 615.1.

To a solution of tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(98) (3.3 g, 5.4 mmol) in THF/EtOH/H₂O (24 mL/12 mL/6 mL) was added ironpowder (3.0 g, 54 mmol) and NH₄Cl (5.8 g, 108 mmol). The reactionmixture was heated at 50° C. for 4 hrs under N₂. After cooled down tor.t., the reaction mixture was filtered through a pad of Celite. Thefiltrate was extracted with EtOAc (50 mL×3), washed with water andbrine, dried over Na₂SO₄, and concentrated in vacuo to give tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(99) (3.0 g, 96%) as a brown oil. LC-MS (ESI): m/z (M+1) 585.2.

To a stirred solution of tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(99) (3.0 g, 5.1 mmol) and TEA (1.4 mL, 10 mmol) in anhydrous DCM (50mL) at 0° C. and under N₂ atmosphere was added a solution of triphosgen(763 mg, 2.6 mmol) in anhydrous DCM (10 mL) over 1 hr. After thestirring was continued for 1 hr, the reaction mixture was quenched withwater (100 mL). The layers were separated, and the organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by column chromatography (silica gel, 0to 20% ethyl acetate in petroleum ether) to give tert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(100) (1.9 g, 61%) as a brown solid. LC-MS (ESI): m/z (M+1) 611.3.

To a mixture of tert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(100) (800 mg, 1.3 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (800 mg, 20wt %) and 3 drops of con. HCl. The resulting mixture was purged with H₂(2×) before heated to 60° C. overnight under H₂ atmosphere. The mixturewas cooled to r.t., filtered through a Celite pad, and the solvent wasremoved in vacuo to give tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(101) (527 mg, 94%) as a white solid. LC-MS (ESI): m/z (M+1) 430.2.

To a mixture of tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate (101) (527 mg, 1.2 mmol) and 4 A MS (300 mg) inanhydrous DMF (15 mL) were added 3-methoxy-4-methylphenylboronic acid(612 mg, 3.7 mmol), Cu(OAc)₂ (224 mg, 1.2 mmol) and pyridine (0.6 mL,7.2 mmol). The reaction mixture was heated at 37° C. overnight under O₂atmosphere before filtered through a Celite pad. The filtrate wasdiluted with water (50 mL), extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with water and brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography (silicagel, 0 to 5% methanol in methylene chloride) to give tert-butyl5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(102) (122 mg, 18%) as a brown oil. LC-MS (ESI): m/z (M+1) 551.1.

To a solution of tert-butyl5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl(methyl)carbamate(102) (122 mg, 0.22 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise.The reaction mixture was stirred at rt for 1 hr before concentrated. Theresidue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to give6-amino-7-(3-methoxy-4-methylphenyl)-9-(4-(2-methoxyethoxy)-3-(methylamino)phenyl)-7H-purin-8(9H)-one (103) (100 mg, 100%) as a brown oil. LC-MS(ESI): m/z (M+1) 451.2.

To a suspension of (E)-4-(dimethylamino)but-2-enoic acid hydrochloridesalt (90 mg, 0.54 mmol) in anhydrous acetonitrile (5 mL) was added 1drop of DMF before introducing (COCl)₂ (0.5 mL, 5.3 mmol). The resultingmixture was stirred at room temperature for 1 hr. The solvent wasevaporated. The freshly generated acid chloride was dissolved inanhydrous DCM (2 mL) and introduced to the solution of6-amino-7-(3-methoxy-4-methylphenyl)-9-(4-(2-methoxyethoxy)-3-(methylamino)phenyl)-7H-purin-8(9H)-one(103) (100 mg, 0.24 mmol) in DCM (3 mL). The reaction mixture wasstirred at room temperature for 1 hr before quenched with MeOH (2 mL).Solvents were removed and the residue was pre-purified by columnchromatography (silica gel, 0 to 10% methanol in methylene chloride(0.3% Et₃N)) followed by preparative HPLC (RP, C18, 10 to 95%acetonitrile in water (0.2% NH₃.H₂O)) to give(E)-N-(5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(104) (26 mg, 21%) as a white solid. LC-MS (ESI): m/z (M+1) 562.3. ¹HNMR (400 MHz, DMSO) δ 8.08 (s, 1H), 7.63 (d, J=8.7 Hz, 1H), 7.57-7.48(m, 1H), 7.32 (d, J=8.4 Hz, 2H), 7.10 (s, 1H), 6.99 (d, J=7.8 Hz, 1H),6.68-6.52 (m, 1H), 5.86 (d, J=15.3 Hz, 1H), 5.69 (s, 2H), 4.29-4.09 (m,J=5.0 Hz, 2H), 3.80 (s, 3H), 3.62 (t, J=4.5 Hz, 2H), 3.27 (s, 3H), 3.13(s, 3H), 2.92-2.80 (m, 2H), 2.21 (s, 3H), 2.02 (s, 6H).

Example 33 Synthesis of(E)-N-(5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl)-4-(dimethylamino)but-2-enamide(112)

In a similar manner as described in Example 32, tert-butyl5-amino-2-(2-methoxyethoxy)phenylcarbamate (105) (1.58 g, 100%) wasprepared as a brown oil starting from tert-butyl2-(2-methoxyethoxy)-5-nitrophenylcarbamate (95) (1.75 g). LC-MS (ESI):m/z (M+1) 283.1.

In a similar manner as described in Example 32, tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenylcarbamate(106) (3.4 g, 100%) was prepared as a brown oil starting from tert-butyl5-amino-2-(2-methoxyethoxy)phenylcarbamate (105) (1.58 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1). LC-MS (ESI): m/z(M+1) 601.3.

In a similar manner as described in Example 32, tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenylcarbamate(107) (3.0 g, 94%) was prepared as a brown oil starting from tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenylcarbamate(106) (3.36 g). LC-MS (ESI): m/z (M+1) 569.2.

In a similar manner as described in Example 32, tert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(108) (1.9 g, 61%) was prepared as a brown oil starting from tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-(2-methoxyethoxy)phenylcarbamate(107) (3.0 g). LC-MS (ESI): m/z (M+1) 597.2.

In a similar manner as described in Example 32, tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(109) (462 mg, 83%) was prepared as a brown solid starting fromtert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(108) (800 mg). LC-MS (ESI): m/z (M+1) 417.1.

In a similar manner as described in Example 32, tert-butyl5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(110) (258 mg, 43%) was prepared as a brown oil starting from tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(109) (462 mg) and 3-methoxy-4-methylphenylboronic acid (553 mg). LC-MS(ESI): m/z (M+1) 537.3.

In a similar manner as described in Example 32,6-amino-9-(3-amino-4-(2-methoxyethoxy)phenyl)-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(111) (209 mg, 100%) was prepared as a brown oil starting fromtert-butyl5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenylcarbamate(110) (258 mg). LC-MS (ESI): m/z (M+1) 437.2.

In a similar manner as described in Example 32,(E)-N-(5-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-2-(2-methoxyethoxy)phenyl)-4-(dimethylamino)but-2-enamide(112) (31 mg, 12%) was prepared as a white solid starting from6-amino-9-(3-amino-4-(2-methoxyethoxy)phenyl)-7-(3-methoxy-4-methylphenyl)-7H-purin-8(9H)-one(111) (209 mg). LC-MS (ESI): m/z (M+1) 548.3. ¹H NMR (400 MHz, DMSO) δ9.25 (s, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.36-7.17 (m, 3H), 7.15 (s,1H), 7.02 (d, J=6.2 Hz, 1H), 6.75-6.63 (m, 1H), 6.50 (d, J=15.4 Hz, 1H),5.65 (s, 2H), 4.30-4.18 (m, 2H), 3.80 (s, 3H), 3.76-3.70 (m, 2H), 3.33(s, 3H), 3.06 (d, J=5.7 Hz, 2H), 2.21 (s, 3H), 2.17 (s, 6H).

Example 34 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropylamino)but-2-enamide(116)

To a solution of (E)-methyl 4-bromobut-2-enoate (6 g, 33.5 mmol) in THF(60 mL) at 0° C. and under N₂ atmosphere was added a solution of lithiumhydroxide monohydrate (1.83 g, 43.6 mmol) in water (20 mL) dropwise over15 min. The resulting mixture was stirred at 0° C. for 3 hrs. Cold water(150 mL) and petroleum ether (200 mL) were then introduced and thestirring was continued at 0° C. for 10 min. The layers were separated.The aqueous layer was acidified with con. HCl at 0° C. to pH˜1 and wasextracted with DCM (80 mL×3). The combined organic extracts were driedover Na₂SO₄ filtered and evaporated under reduced pressure to give(E)-4-bromobut-2-enoic acid (113) (4.5 g, 82% yield) as a yellow solid.

To a solution of (E)-4-bromobut-2-enoic acid (113) (162 mg, 0.98 mmol)and a drop of DMF in anhydrous DCM (3 mL) was added oxalyl chloride (250mg, 1.96 mmol) dropwise. The resulting mixture was stirred at r.t. for 1hour. The solvent was removed in vacuo to give (E)-4-bromobut-2-enoylchloride (114) (quant.) and used for next step directly.

To a solution of6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7)(200 mg, 0.49 mmol) in anhydrous DCM (3 mL) at 0° C. was added freshlygenerated (E)-4-bromobut-2-enoyl chloride (114) (179 mg, 0.98 mmol) inDCM (2 mL) dropwise. The resulting mixture was stirred at r.t. for 1hour before it was quenched with MeOH (0.5 mL) and water (5 mL). Thereaction mixture was then extracted with DCM (3 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-bromobut-2-enamide(115) (quant.) as a light yellow oil. LC-MS (ESI): m/z (M/M+2)557.4/559.4.

To a suspension of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-bromobut-2-enamide(115) (273 mg, 0.49 mmol) and K₂CO₃ (200 mg, 1.47 mmol) in MeCN (5 mL)was added cyclopropanamine (56 mg, 0.98 mmol). The resulting mixture wasstirred at r.t. overnight. The solid suspension was filtered off, andthe filtrate was concentrated in vacuo. The residue was pre-purified bycolumn chromatography (0 to 10% MeOH in DCM) followed by preparativeHPLC purification (RP C18, 10 to 95% acetonitrile in water (0.2%NH₃.H₂O)) to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropylamino)but-2-enamide(116) (29 mg, 3 step yield 11%) as a white solid. LC-MS (ESI): m/z (M+1)534.4. ¹H NMR (400 MHz, DMSO) δ 10.25 (s, 1H), 8.34-8.21 (m, 1H), 8.10(s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.46-7.40(m, 3H), 7.30 (s, 1H), 7.22-7.11 (m, 5H), 6.88-6.75 (m, 1H), 6.24 (d,J=15.4 Hz, 1H), 5.82 (s, 2H), 3.36 (d, J=4.2 Hz, 2H), 2.13-2.02 (m, 1H),0.41-0.30 (m, 2H), 0.28-0.16 (m, 2H).

Example 35 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropylamino)-N-methylbut-2-enamide(118)

In a similar manner as described in Example 34,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-bromo-N-methylbut-2-enamide(117) (100 mg, 62%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (120 mg). LC-MS (ESI): m/z (M/M+2) 571.4/573.4.

In a similar manner as described in Example 34,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropylamino)-N-methylbut-2-enamide(118) (32 mg, 34%) was prepared as a white solid starting from(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-bromo-N-methylbut-2-enamide(117) (100 mg). LC-MS (ESI): m/z (M+1) 540.2. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.62-7.56 (m, 2H), 7.49 (d, J=8.8Hz, 2H), 7.43 (t, J=7.9 Hz, 2H), 7.34 (d, J=8.6 Hz, 1H), 7.18-7.12 (m,5H), 6.78-6.70 (m, 1H), 6.03 (d, J=15.3 Hz, 1H), 5.87 (s, 2H), 3.28 (s,3H), 3.25-3.17 (m, 3H), 2.01-1.86 (m, 1H), 0.25-0.19 (m, 2H), 0.13-0.04(m, 2H).

Example 36 Synthesis of(S,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(123)

To a suspension of (S)-tetrahydrofuran-3-amine hydrochloride (500 mg, 4mmol) and K₂CO₃ (830 mg, 6 mmol) in MeCN (10 mL) were added (E)-methyl4-bromobut-2-enoate (663 mg, 3.9 mmol). The mixture was stirred at roomtemperature for 3 hrs. The solid was filtered off, and the filtrate wasconcentrated in vacuo. The residue was purified by columnchromatographic (silica gel, 0 to 50% ethyl acetate in petroleum ether)to give (S,E)-methyl 4-(tetrahydrofuran-3-ylamino)but-2-enoate (119)(500 mg, 69%) as light yellow oil. LC-MS (ESI): m/z (M+1) 186.1

To a solution of (S,E)-methyl 4-(tetrahydrofuran-3-ylamino)but-2-enoate(119) (400 mg, 2.16 mmol) and HCHO (38%, 854 mg, 10.8 mmol) in DCM (8mL) was added NaBH(OAc)₃ (1.37 g, 6.48 mmol). The resulting mixture wasstirred at r.t. for 1 hr before quenched with water (0.5 mL). Thesolvent was removed in vacuo and the residue was purified by columnchromatography (silica gel, 0 to 50% ethyl acetate in petroleum ether)to give (S,E)-methyl 4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoate(120) (350 mg, 81%) as light yellow oil. LC-MS (ESI): m/z (M+1) 200.1.

To a stirred solution of (S,E)-methyl4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoate (120) (350 mg, 1.76mmol) in THF (3 mL) was added a solution of lithium hydroxidemonohydrate (148 mg, 3.51 mmol) in water (2 mL) dropwise. The resultingmixture was stirred at r.t. for 1 h and subsequently was acidified withcon. HCl to pH˜1. The solvent was directly removed in vacuo to givecrude (S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (121)(quant.) mixed with LiCl salt. LC-MS (ESI): m/z (M+1) 186.1.

In a similar manner as described in Example 34,(S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoyl chloride (122)(quant.) was prepared as a yellow solid starting from(S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (121) (55mg).

In a similar manner as described in Example 34,(S,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(123) (22 mg, 15%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (100 mg). LC-MS (ESI): m/z (M+1) 592.3. ¹H NMR (400 MHz, DMSO) δ8.12 (s, 1H), 7.76-7.54 (m, 3H), 7.54-7.30 (m, 5H), 7.25-7.06 (m, 5H),6.71-6.60 (m, 1H), 6.12-5.98 (m, 1H), 5.87 (br, 2H), 3.75-3.64 (m, 1H),3.61-3.55 (m, 1H), 3.54-3.46 (m, 1H), 3.42-3.33 (m, 1H), 3.28 (s, 3H),3.11-2.90 (m, 3H), 2.01 (s, 3H), 1.90-1.73 (m, 1H), 1.70-1.54 (m, 1H).

Example 37 Synthesis of(R,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(129)

In a similar manner as described in Example 36, (R,E)-methyl4-(tetrahydrofuran-3-ylamino)but-2-enoate (124) (330 mg, 68%) wasprepared as a white solid starting from (E)-methyl 4-bromobut-2-enoate(466 mg) and (R)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (676mg). LC-MS (ESI): m/z (M+1) 186.1.

In a similar manner as described in Example 36, (R,E)-methyl4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoate (125) (320 mg, 100%)was prepared as a light yellow oil starting from (R,E)-methyl4-(tetrahydrofuran-3-ylamino)but-2-enoate (124) (300 mg). LC-MS (ESI):m/z (M+1) 200.1.

In a similar manner as described in Example 36,(R,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (126)(quant.) was prepared as a light yellow oil starting from (R,E)-methyl4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoate (125) (320 mg). LC-MS(ESI): m/z (M+1) 186.1.

In a similar manner as described in Example 34,(R,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoyl chloride (127)(quant.) was prepared as a yellow solid starting from(R,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (126) (55mg).

In a similar manner as described in Example 34,(R,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(129) (40 mg, 28%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (100 mg). LC-MS (ESI): m/z (M+1) 592.2. ¹H NMR (400 MHz, DMSO) δ8.14 (s, 1H), 7.74-7.59 (m, 3H), 7.50-7.37 (m, 5H), 7.21-7.14 (m, 4H),6.70-6.60 (m, 1H), 6.42-6.22 (m, 1H), 5.92 (br, 2H), 4.02-3.75 (m, 5H),3.67-3.44 (m, 2H), 3.31 (s, 3H), 2.60 (s, 3H), 2.22-1.94 (m, 2H).

Example 38 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-((2-methoxyethyl)(methyl)amino)-N-methylbut-2-enamide(134)

In a similar manner as described in Example 36, (E)-methyl4-(2-methoxyethylamino)but-2-enoate (130) (800 mg, 82%) was prepared asa light yellow oil starting from (E)-methyl 4-bromobut-2-enoate (1 g)and 2-methoxyethanamine (504 mg). LC-MS (ESI): m/z (M+1) 174.1.

In a similar manner as described in Example 36, (E)-methyl4-(2-methoxyethyl(methyl)amino)but-2-enoate (131) (330 mg, 72%) wasprepared as a light yellow oil starting from (E)-methyl4-(2-methoxyethylamino)but-2-enoate (130) (500 mg). LC-MS (ESI): m/z(M+1) 188.1.

In a similar manner as described in Example 36,(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid (132) (quant.) wasprepared as a white solid starting from (E)-methyl4-(2-methoxyethyl(methyl)amino)but-2-enoate (131) (330 mg). LC-MS (ESI):m/z (M+1) 172.2.

In a similar manner as described in Example 34,(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoyl chloride (133) (quant.)was prepared as a yellow solid starting from(E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid (132) (133 mg).

In a similar manner as described in Example 34,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-((2-methoxyethyl)(methyl)amino)-N-methylbut-2-enamide(134) (32 mg, 23%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (100 mg). LC-MS (ESI): m/z (M+1) 580.2. ¹H NMR (400 MHz, DMSO) δ9.74 (s, 1H), 8.14 (s, 1H), 7.85-7.59 (m, 3H), 7.51-7.37 (m, 4H),7.23-7.10 (m, 4H), 6.66 (dd, J=14.8, 7.1 Hz, 1H), 6.36-6.22 (m, 1H),5.93 (br, 2H), 3.95-3.70 (m, 2H), 3.64-3.44 (m, 2H), 3.31 (s, 3H),3.27-3.02 (m, 5H), 2.66 (s, 3H).

Example 39 Synthesis of(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(147)

To a stirred solution of 2-methoxyethanol (3.58 g, 47.2 mmol) inanhydrous DMF (50 mL) at 0° C. were added NaH (60%, 3.14 g, 78.6 mmol).The mixture was stirred at room temperature for 10 min before1,3-difluoro-5-nitrobenzene (452 mg, 2.4 mmol) was introduced. After theresulting mixture was stirred at rt for 2 hr, the reaction was quenchedwith water (100 mL) and extracted with EA (50 mL×3). Combined organiclayers were washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (silica gel, 0to 20% ethyl acetate in petroleum) to provide1-fluoro-3-(2-methoxyethoxy)-5-nitrobenzene (135) (6.4 g, 95%) as yellowoil. LC-MS (ESI): m/z (M+1) 216.1.

To a solution of 1-fluoro-3-(2-methoxyethoxy)-5-nitrobenzene (135) (1 g,4.65 mmol) and (4-methoxyphenyl)methanamine (3.18 g, 23.2 mmol) in DMSO(14 mL) was added K₂CO₃ (1.93 g, 13.95 mmol). The mixture was stirredunder microwave at 180° C. for 1 hr. After cooled down to r.t., thereaction mixture was poured into water (100 mL) and extracted with EA(30 mL×3). Combined organic layers were washed with brine, dried overNa₂SO₃ and concentrated in vacuo. The residue was purified by columnchromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether)to give N-(4-methoxybenzyl)-3-(2-methoxyethoxy)-5-nitroaniline (136)(530 mg, 35%) as red oil. LC-MS (ESI): m/z (M+1) 333.2.

N-(4-Methoxybenzyl)-3-(2-methoxyethoxy)-5-nitroaniline (136) (3.6 g,10.8 mmol) was stirred in TFA (15 mL) at r.t. overnight. The solvent wasremoved in vacuo and the residue was purified by column chromatography(silica gel, 0 to 30% ethyl acetate in petroleum ether) to give3-(2-methoxyethoxy)-5-nitroaniline (137) (1.84 g, 80%) as a yellow oil.LC-MS (ESI): m/z (M+1) 213.2.

To a solution of 3-(2-methoxyethoxy)-5-nitroaniline (137) (1.83 g, 8.63mmol), Et₃N (2 mL) and (Boc)₂O (3.76 g, 17.26 mmol) in anhydrous THF (20mL) was added DMAP (cat.). The mixture was stirred at 65° C. under N₂overnight. After the reaction mixture was cool down to r.t., the solventwas removed in vacuo and the residue was purified by columnchromatography (silica gel, 0 to 20% ethyl acetate in petroleum ether)to afford tert-butyl 3-(2-methoxyethoxy)-5-nitrophenylcarbamate (138)(1.78 g, 66%). LC-MS (ESI): m/z (M+1) 313.2.

In a similar manner as described in Example 32, tert-butyl3-(2-methoxyethoxy)-5-nitrophenyl(methyl)carbamate (139) (1.25, 68%) wasprepared as an orange oil starting from tert-butyl3-(2-methoxyethoxy)-5-nitrophenylcarbamate (138) (1.78 g).

tert-Butyl 3-(2-methoxyethoxy)-5-nitrophenyl(methyl)carbamate (139)(1.25 g, 3.8 mmol) and Pd/C (125 mg) was suspended in MeOH (50 mL). Thereaction mixture was stirred at r.t. under H₂ atmosphere for 2 hrs. Themixture was filtered and the filtrate was concentrated in vacuo to givetert-butyl 3-amino-5-(2-methoxyethoxy)phenyl(methyl)carbamate (140)(1.13 g, quant.) as a yellow oil. LC-MS (ESI): m/z (M+1) 297.3.

In a similar manner as described in Example 32, tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(141) (2.0 g, 85%) was prepared as a yellow solid starting fromtert-butyl 3-amino-5-(2-methoxyethoxy)phenyl(methyl)carbamate (140)(1.13 g). LC-MS (ESI): m/z (M+1) 615.2.

In a similar manner as described in Example 32, tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(142) (1.35 g, 25%) was prepared as a yellow solid starting fromtert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(141) (2.0 g). LC-MS (ESI): m/z (M+1) 585.3.

In a similar manner as described in Example 32, tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(143) (1.3 g, 93%) was prepared as a yellow solid starting fromtert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(142) (1.35 g). LC-MS (ESI): m/z (M+1) 611.3.

In a similar manner as described in Example 32, tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(144) (800 mg, 89%) was prepared as a brown solid starting fromtert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(143) (1.3 g). LC-MS (ESI): m/z (M+1) 431.3.

In a similar manner as described in Example 32, tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(145) (660 mg, 25%) was prepared as a light yellow solid starting fromtert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(144) (800 mg). LC-MS (ESI): m/z (M+1) 551.3.

In a similar manner as described in Example 32,6-amino-7-(3-methoxy-4-methylphenyl)-9-(3-(2-methoxyethoxy)-5-(methylamino)phenyl)-7H-purin-8(9H)-one(146) (quant.) was prepared as a white solid starting from tert-butyl3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl(methyl)carbamate(145) (660 mg). LC-MS (ESI): m/z (M+1) 451.2.

In a similar manner as described in Example 32,(E)-N-(3-(6-amino-7-(3-methoxy-4-methylphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-(2-methoxyethoxy)phenyl)-4-(dimethylamino)-N-methylbut-2-enamide(147) (49 mg, 40%) was prepared as a white solid starting from6-amino-7-(3-methoxy-4-methylphenyl)-9-(3-(2-methoxyethoxy)-5-(methylamino)phenyl)-7H-purin-8(9H)-one(146) (100 mg). LC-MS (ESI): m/z (M+1) 562.3. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.36-7.26 (m, 2H), 7.20 (s, 1H), 7.11 (d, J=1.8 Hz, 1H),7.02-6.95 (m, 2H), 6.64 (dt, J=15.2, 6.1 Hz, 1H), 6.05 (d, J=15.1 Hz,1H), 5.71 (s, 2H), 4.18-4.11 (m, 2H), 3.80 (s, 3H), 3.69-3.62 (m, 2H),3.26 (s, 3H), 2.91 (d, J=5.6 Hz, 2H), 2.21 (s, 3H), 2.04 (s, 6H).

Example 40 Synthesis of(E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(151)

To a solution of 4-bromophenol (500 mg, 2.89 mmol),3-fluorophenylboronic acid (809 mg, 5.78 mmol) and Et₃N (2 mL, 14.45mmol) in DCM was added Cu(OAc)₂ (525 mg, 2.89 mmol) and molecular sieve(4 A, 1 g). The mixture was stirred at room temperature overnight underO₂ atmosphere. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatography(silica gel, 0 to 30% ethyl acetate in petroleum ether) to give1-(4-bromophenoxy)-3-fluorobenzene (148) (350 mg, 45%) as yellow solid.

To a solution of 1-(4-bromophenoxy)-3-fluorobenzene (148) (345 mg, 1.3mmol) in THF (10 mL) at −78° C. and under N₂ atmosphere was added n-BuLi(2.5 M, 0.7 mL, 1.7 mmol) dropwise. The mixture was stirred at −78° C.for 20 min before triisopropyl borate (0.35 mL) was added. The mixturewas allowed warm to room temperature and stirred for 3 hrs. The reactionwas quenched with HCl (1N) and extracted with EA (5 mL×3). Combinedorganic layer was washed with brine and dried over Na₂SO₄. The solventwas removed in vacuo to give 4-(3-fluorophenoxy) phenylboronic acid(149) (150 mg, 50%) as white solid. LC-MS (ESI): m/z (M−1) 231.1.

In a similar manner as described in Example 1, tert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(150) (80 mg, 43%) was prepared as a yellow solid starting fromtert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(24) (525 mg). LC-MS (ESI): m/z (M+1) 543.3.

In a similar manner as described in Example 1,(E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(151) (26 mg, 33%) was prepared as a white solid starting fromtert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(150) (80 mg). LC-MS (ESI): m/z (M+1) 543.3. ¹H NMR (400 MHz, DMSO) δ8.12 (s, 1H), 7.71-7.56 (m, 3H), 7.51 (d, J=8.7 Hz, 2H), 7.44 (dd,J=15.3, 8.1 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H),7.08-6.95 (m, 3H), 6.75-6.60 (m, 1H), 6.09-5.87 (m, 3H), 3.30 (s, 3H),3.12 (d, J=5.6 Hz, 2H), 2.12 (s, 3H), 1.68-1.51 (m, 1H), 0.36-0.28 (m,2H), 0.25-0.13 (m, 2H).

Example 41 Synthesis of(E)-6-amino-9-(4-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(161)

To a solution of 2-amino-4-nitrophenol (5.0 g, 32.5 mmol) in anhydrousDMF (100 mL) was added K₂CO₃ (13.4 g, 97 mmol) and 1,2-dibromoethane(3.3 mL, 39 mmol). The resulting mixture was stirred at 125° C. under N₂overnight. After cooling down to r.t., the reaction mixture wasconcentrated, diluted with water (100 mL), and extracted with EtOAc (50mL×3). The combined organic layer was washed with water and brine, driedover Na₂SO₄, and concentrated. The residue was purified by columnchromatography (silica gel, 0 to 30% ethyl acetate in petroleum ether)to give 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (152) (2.0 g, 34%)as a yellow solid. LC-MS (ESI): m/z (M+1) 181.2.

A solution of 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (152) (2.0 g,11.1 mmol) in anhydrous DCM (50 mL) was treated with Boc₂O (6.2 g, 28.4mmol), pyridine (3.6 mL, 45 mmol), and catalytic DMAP (40 mg). Themixture was stirred at r.t. overnight and then diluted with water (100mL), extracted with EtOAc (50 mL×3). The combined organic layer waswashed with 10% citric acid solution and brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography (silicagel, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl6-nitro-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (153) (1.0 g, 32%) asa yellow solid. LC-MS (ESI): m/z (M+1) 281.1.

To a solution of tert-butyl6-nitro-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (153) (1.0 g, 3.6mmol) in THF/MeOH/H₂O (24 mL/12 mL/6 mL) was added iron powder (2.0 g,36 mmol) and NH₄Cl (3.9 g, 72 mmol). The resulting suspension was heatedat 50° C. for 5 hrs under N₂. After cooled down to r.t., the reactionmixture was filtered through a pad of Celite. The filtrate was extractedwith EtOAc (50 mL×3), washed with water and brine, dried over Na₂SO₄,and concentrated in vacuo to give tert-butyl6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (154) (0.8 g, 89%) asa brown oil. LC-MS (ESI): m/z (M+1) 251.1.

To a solution of tert-butyl6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (154) (0.8 g, 3.2mmol) and TEA (0.9 mL, 6.4 mmol) in dioxane (20 mL) was addedN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (1.13 g, 3.2 mmol).The reaction mixture was heated at 70° C. overnight under N₂, beforewater (100 mL) was introduced. The resulting mixture was extracted withEtOAc (50 mL×3), the combined organic layer was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, 0 to 20% ethyl acetate in petroleumether) to give tert-butyl6-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(155) (1.8 g, 99%) as a brown oil. LC-MS (ESI): m/z (M+1) 569.1.

To a solution of tert-butyl6-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (155) (1.8 g, 3.2 mmol) inTHF/EtOH/H₂O (24 mL/12 mL/6 mL) was added Fe powder (1.77 g, 32 mmol)and NH₄Cl (3.46 g, 64 mmol). The resulting suspension was heated at 50°C. for 5 hrs under N₂. After cooled down to r.t., the reaction mixturewas filtered through a pad of Celite. The filtrate was extracted withEtOAc (50 mL×3), washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo to afford tert-butyl 6-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (156)(1.7 g, quant.) as a brown oil. LC-MS (ESI): m/z (M+1) 539.0.

To a stirred solution of tert-butyl6-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(156) (1.7 g, 3.2 mmol) and TEA (0.9 mL, 6.4 mmol) in anhydrous DCM (50mL) at 0° C. and under N₂ atmosphere was added a solution of triphosgene(475 mg, 1.6 mmol) in anhydrous DCM (10 mL) over 1 hr. The stirring wascontinued for 1 hr before the reaction was quenched with water (100 mL).The layers was separated, the organic layer was washed with water andbrine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, 0 to 30% ethyl acetate inpetroleum ether) to give tert-butyl6-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(157) (1.5 g, 85%) as a brown solid. LC-MS (ESI): m/z (M+1) 565.2.

To a mixture of tert-butyl6-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(157) (0.8 g, 1.4 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (800 mg, 20wt %) and 3 drops of con. HCl. The resulting mixture was purged with H₂(2×) before heated to 60° C. overnight under H₂ atmosphere. The reactionmixture was cooled down to r.t., filtered through a Celite pad, and thefiltrate was concentrated down in vacuo to give tert-butyl6-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(158) (0.5 g, 92%) as a yellow solid. LC-MS (ESI): m/z (M+1) 385.0.

To a mixture of tert-butyl6-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(158) (0.5 g, 1.3 mmol) and 4 A MS (300 mg) in dry DMF (20 mL) wereadded 4-phenoxyphenylboronic acid (836 mg, 3.9 mmol), Cu(OAc)₂ (237 mg,1.3 mmol) and pyridine (0.6 mL, 7.8 mmol). The reaction mixture washeated at 37° C. overnight under O₂ atmosphere, filtered through aCelite pad. The filtrate was diluted with water (80 mL), extracted withEtOAc (30 mL×3). The combined organic layer was washed with water andbrine, dried over Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography (silica gel, 0 to 5% methanol in methylenechloride) to give tert-butyl6-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(159) (663 mg, 92%) as a brown oil. LC-MS (ESI): m/z (M+1) 553.2.

To a solution of tert-butyl6-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(159) (663 mg, 1.2 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise.The reaction mixture was stirred at rt for 1 hr before concentrated. Theresidue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to give6-amino-9-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(160) (424 mg, 78%) as a brown oil. LC-MS (ESI): m/z (M+1) 453.1.

To a suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acidhydrochloride salt (169 mg, 0.88 mmol) in anhydrous acetonitrile (5 mL)was added 1 drop of DMF before introducing (COCl)₂ (1.0 mL, 10.6 mmol).The resulting mixture was stirred at room temperature for 1 hr. Thesolvents were evaporated. The freshly generated acid chloride wasdissolved in dry DCM (2 mL) and introduced to the solution of6-amino-9-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(160) (200 mg, 0.44 mmol) in DCM (5 mL). Resulting mixture was stirredat room temperature for 1 hr before quenched with MeOH (2 mL). Solventwas removed and the residue was pre-purified by column chromatography(silica gel, 0 to 10% methanol in methylene chloride (0.3% Et₃N))followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water(0.2% NH₃.H₂O)) to give(E)-6-amino-9-(4-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(161) (19 mg, 7%) as a white solid. LC-MS (ESI): m/z (M+1) 590.1. ¹H NMR(400 MHz, DMSO) δ 9.60 (s, 1H), 8.13 (s, 1H), 7.52-7.40 (m, 4H),7.40-7.34 (m, 1H), 7.23-7.11 (m, 5H), 7.08 (d, J=8.8 Hz, 1H), 7.02-6.88(m, 1H), 6.82-6.66 (m, 1H), 5.86 (s, 2H), 4.36 (t, 2H), 4.09-3.89 (m,4H), 2.88-2.63 (m, 4H), 0.93-0.58 (m, 4H).

Example 42 Synthesis of(E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(171)

To a solution of 2-methoxy-5-nitroaniline (5.0 g, 30 mmol) in EtOH (50mL) was added Boc anhydride (13 g, 60 mmol). The reaction mixture wasstirred at r.t. for 24 h under N₂ atmosphere. The solvents were removedin vacuo. The residue was washed with petroleum ether, dried undervacuum to give tert-butyl 2-methoxy-5-nitrophenylcarbamate (162) (6.0 g,75%) as a yellow solid. LC-MS (ESI): m/z (M+1) 269.0.

To a suspension of NaH (60% dispersion in mineral oil, 1.3 g, 33 mmol)in dry THF (40 mL) at 0° C. was added a solution of tert-butyl2-methoxy-5-nitrophenylcarbamate (162) (6.0 g, 22 mmol) in THF (40 mL).The mixture was stirred at 0° C. for 0.5 hour before CH₃I (2.5 mL, 37mmol) was added dropwise. Stirring was continued at room temperatureovernight, then concentrated under reduced pressure. The residue wasdiluted with water (200 mL), extracted with EtOAc (80 mL×3). Thecombined organic layer was washed with water and brine, dried overNa₂SO₄, and concentrated in vacuo to afford tert-butyl2-methoxy-5-nitrophenyl(methyl)carbamate (163) (6.3 g, quant.) as abrown solid. LC-MS (ESI): m/z (M+1) 283.2.

In a similar manner as described in Example 41, tert-butyl5-amino-2-methoxyphenyl(methyl)carbamate (164) (5.6 g, 100%) wasprepared as a brown solid starting from tert-butyl2-methoxy-5-nitrophenyl(methyl)carbamate (163) (6.3 g). LC-MS (ESI): m/z(M+1) 253.1.

In a similar manner as described in Example 41, tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-methoxyphenyl(methyl)carbamate(165) (8.0 g, 63%) was prepared as a brown oil starting from tert-butyl5-amino-2-methoxyphenyl(methyl)carbamate (164) (5.6 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (7.8 g). LC-MS (ESI):m/z (M+1) 571.2.

In a similar manner as described in Example 41, tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-methoxyphenyl(methyl)carbamate(166) (6.9 g, 91%) was prepared as a brown solid starting fromtert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-methoxyphenyl(methyl)carbamate(165) (8.0 g). LC-MS (ESI): m/z (M+1) 541.1.

In a similar manner as described in Example 41, tert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate (167) (6.0 g, 83%) was prepared as a brown oil starting fromtert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-methoxyphenyl(methyl)carbamate(166) (6.9 g). LC-MS (ESI): m/z (M+1) 567.0.

In a similar manner as described in Example 41, tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(168) (0.5 g, 92%) was prepared as a brown solid starting fromtert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate (167) (0.8 g). LC-MS (ESI): m/z (M+1) 387.2.

In a similar manner as described in Example 41, tert-butyl5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(169) (300 mg, 42%) was prepared as a brown oil starting from tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(168) (500 mg) and 4-phenoxyphenylboronic acid (832 mg). LC-MS (ESI):m/z (M+1) 555.1.

In a similar manner as described in Example 41,6-amino-9-(4-methoxy-3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(170) (217 mg, 100%) was prepared as a brown oil starting fromtert-butyl5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(169) (265 mg). LC-MS (ESI): m/z (M+1) 455.1.

In a similar manner as described in Example 41,(E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(171) (34 mg, 26%) was prepared as a white solid starting from6-amino-9-(4-methoxy-3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(170) (100 mg). LC-MS (ESI): m/z (M+1) 592.1. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.73-7.63 (m, 1H), 7.58 (s, 1H), 7.49-7.40 (m, 4H), 7.34(d, J=9.0 Hz, 1H), 7.22-7.11 (m, 5H), 6.71-6.59 (m, 1H), 6.14 (d, J=14.9Hz, 1H), 5.88 (s, 2H), 3.98-3.88 (m, 2H), 3.86 (s, 3H), 3.16 (s, 3H),2.78-2.65 (m, 4H), 0.87-0.67 (m, 4H).

Example 43 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(181)

In a similar manner as described in Example 42, tert-butyl4-methoxy-3-nitrophenylcarbamate (172) (3.2 g, 100%) was prepared as ayellow solid starting from 4-methoxy-3-nitroaniline (2.0 g). LC-MS(ESI): m/z (M+1) 269.1.

In a similar manner as described in Example 42, tert-butyl4-methoxy-3-nitrophenyl(methyl)carbamate (173) (3.4 g, 100%) wasprepared as a brown solid starting from tert-butyl4-methoxy-3-nitrophenylcarbamate (172) (3.2 g). LC-MS (ESI): m/z (M+1)283.2.

In a similar manner as described in Example 41, tert-butyl3-amino-4-methoxyphenyl(methyl)carbamate (174) (3.0 g, 100%) wasprepared as a brown solid starting from tert-butyl4-methoxy-3-nitrophenyl(methyl)carbamate (173) (3.4 g). LC-MS (ESI): m/z(M+1) 253.0.

In a similar manner as described in Example 41, tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-4-methoxyphenyl(methyl)carbamate(175) (6.8 g, 98%) was prepared as a brown oil starting from tert-butyl3-amino-4-methoxyphenyl(methyl)carbamate (174) (3.0 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (4.25 g). LC-MS(ESI): m/z (M+1) 571.0.

In a similar manner as described in Example 41, tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-4-methoxyphenyl(methyl)carbamate(176) (6.1 g, 94%) was prepared as a brown solid starting fromtert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-4-methoxyphenyl(methyl)carbamate(175) (6.8 g). LC-MS (ESI): m/z (M+1) 541.1.

In a similar manner as described in Example 41, tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate (177) (5.4 g, 85%) was prepared as a brown oil starting fromtert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-4-methoxyphenyl(methyl)carbamate(176) (6.1 g). LC-MS (ESI): m/z (M+1) 567.1.

In a similar manner as described in Example 41, tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate(178) (0.9 g, 100%) was prepared as a yellow solid starting fromtert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate (177) (1.3 g). LC-MS (ESI): m/z (M+1) 387.2.

In a similar manner as described in Example 41, tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate(179) (440 mg, 34%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate(178) (902 mg) and 4-phenoxyphenylboronic acid (1.5 g). LC-MS (ESI): m/z(M+1) 555.1.

In a similar manner as described in Example 41,6-amino-9-(2-methoxy-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(180) (360 mg, 100%) was prepared as a brown oil starting fromtert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methoxyphenyl(methyl)carbamate(179) (440 mg). LC-MS (ESI): m/z (M+1) 455.1.

In a similar manner as described in Example 41,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(181) (35 mg, 12%) was prepared as a white solid starting from6-amino-9-(2-methoxy-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(180) (230 mg). LC-MS (ESI): m/z (M+1) 592.1. ¹H NMR (400 MHz, DMSO) δ8.32 (HCOOH), 8.03 (s, 1H), 7.52-7.24 (m, 6H), 7.22-7.09 (m, 6H),6.72-6.58 (m, 1H), 6.02-5.88 (m, 1H), 5.86 (s, 2H), 3.78 (s, 3H), 3.22(s, 3H), 3.10 (d, J=6.0 Hz, 2H), 2.12 (s, 3H), 1.67-1.54 (m, 1H),0.37-0.30 (m, 2H), 0.26-0.17 (m, 2H).

Example 44 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(191)

To a solution of 4-methyl-3-nitroaniline (5.0 g, 33 mmol) in THF (50 mL)was added Boc anhydride (12 g, 55 mmol). The reaction mixture wasrefluxed overnight under N₂ atmosphere. The solvents were removed invacuo. The residue was partitioned between with water (100 mL) and DCM(150 mL). The layers were separated. The organic layer was washed with10% citric acid solution and brine, dried over Na₂SO₄, and concentratedin vacuo to afford tert-butyl 4-methyl-3-nitrophenylcarbamate (182) (8.3g, quant.) as a brown solid. LC-MS (ESI): m/z (M+1) 253.2.

To a suspension of NaH (60% dispersion in mineral oil, 1.98 g, 49.5mmol) in dry THF (40 mL) at 0° C. was added a solution of tert-butyl4-methyl-3-nitrophenylcarbamate (182) (8.3 g, 33 mmol) in THF (40 mL).The resulting mixture was stirred at 0° C. for 0.5 hour before CH₃I (3.0mL, 50 mmol) was introduced dropwise. Stirring was continued at roomtemperature overnight before the reaction was quenched with water (10mL). The mixture was concentrated under reduced pressure. The residuewas treated with water (200 mL), and the crude product was extractedwith EtOAc (80 mL×3). The combined organic layer was washed with waterand brine, dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, 0 to 30% ethyl acetate inpetroleum ether) to give tert-butylmethyl(4-methyl-3-nitrophenyl)carbamate (183) (6.7 g, 77%) as a brownsolid. LC-MS (ESI): m/z (M+1) 267.2.

To a solution of tert-butyl methyl(4-methyl-3-nitrophenyl)carbamate(183) (3.0 g, 11.3 mmol) in THF/MeOH/H₂O (24 mL/12 mL/6 mL) was addediron powder (6.3 g, 113 mmol) and NH₄Cl (12.2 g, 226 mmol). Theresulting mixture was heated at 50° C. for 5 hrs under N₂. After cooleddown to r.t., the reaction mixture was filtered through a pad of Celite.The filtrate was extracted with EtOAc (60 mL×3), and the combinedorganic extract was washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo to give tert-butyl3-amino-4-methylphenyl(methyl)carbamate (184) (2.0 g, 75%) as a brownsolid. LC-MS (ESI): m/z (M+1) 237.1.

To a solution of tert-butyl 3-amino-4-methylphenyl(methyl)carbamate(184) (2.0 g, 8.5 mmol) and TEA (2.3 mL, 17 mmol) in dioxane (40 mL) wasadded N,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (3.0 g, 8.5mmol). The resulting mixture was heated at 70° C. overnight under N₂.Water (100 mL) was introduced to quench the reaction. The reactionmixture was extracted with EtOAc (50 mL×3), and the combined organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by column chromatography (silicagel, 0 to 20% ethyl acetate in petroleum ether) to give tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-4-methylphenyl(methyl)carbamate(185) (2.6 g, 55%) as a brown oil. LC-MS (ESI): m/z (M+1) 555.1.

To a solution of tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-4-methylphenyl(methyl)carbamate(185) (2.6 g, 4.7 mmol) in THF/MeOH/H₂O (24 mL/12 mL/6 mL) was addediron powder (2.6 g, 47 mmol) and NH₄Cl (5.0 g, 94 mmol). The resultingsuspension was heated at 50° C. for 5 hrs under N₂. After cooled to rt,the reaction mixture was filtered through a pad of Celite. The filtratewas extracted with EtOAc (50 mL×3), and the combined organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated invacuo. tert-butyl 3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-4-methylphenyl(methyl)carbamate (186) (2.0 g, 81%)was afforded as a brown oil. LC-MS (ESI): m/z (M−1) 523.0.

To a stirred solution of tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-4-methylphenyl(methyl)carbamate(186) (2.0 g, 3.8 mmol) and TEA (1.1 mL, 7.6 mmol) in anhydrous DCM (50mL) at 0° C. and under N₂ atmosphere was added a solution of triphosgen(564 mg, 1.9 mmol) in anhydrous DCM (10 mL) dropwise over 1 hr. Afterthe stirring was continued for 1 hr, the reaction was quenched withwater (100 mL). The layers were separated. The organic layer was washedwith water and brine, dried over Na₂SO₄, and concentrated in vacuo. Thecrude product was purified by column chromatography (silica gel, 0 to30% ethyl acetate in petroleum ether) to give tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-4-methylphenyl(methyl)carbamate(187) (2.1 g, 100%) as a brown solid. LC-MS (ESI): m/z (M+1) 551.1.

To a mixture of tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-4-methylphenyl(methyl)carbamate(187) (0.8 g, 1.45 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (800 mg, 20wt %) and 3 drops of con. HCl. The resulting mixture was purged with H₂(2×) before heated to 60° C. overnight under H₂ atmosphere. The mixturewas cooled down to r.t., and filtered through a Celite pad. The filtratewas concentrated in vacuo to give tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-4-methylphenyl(methyl)carbamate(188) (538 mg, 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 371.0.

To a mixture of tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-4-methylphenyl(methyl) carbamate(188) (538 mg, 1.45 mmol) and 4 A MS (300 mg) in anhydrous DMF (20 mL)were added 4-phenoxyphenylboronic acid (934 mg, 4.4 mmol), Cu(OAc)₂ (265mg, 1.4 mmol) and pyridine (0.7 mL, 8.7 mmol). The resulting mixture washeated at 37° C. overnight under O₂ atmosphere. After the mixture wasfiltered through a Celite pad, the filtrate was further diluted withwater (80 mL), extracted with EtOAc (30 mL×3). The combined organiclayer was washed with water and brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography (silicagel, 0 to 5% methanol in methylene chloride) to give tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methylphenyl(methyl)carbamate(189) (300 mg, 38%) as a brown oil. LC-MS (ESI): m/z (M+1) 539.1.

To a solution of tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methylphenyl(methyl)carbamate(189) (300 mg, 0.56 mmol) in DCM (4 mL) was added TFA (1 mL) dropwise.The reaction mixture was stirred at r.t. for 1 hr before concentrated.The residue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to give6-amino-9-(2-methyl-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(190) (244 mg, 100%) as a brown oil. LC-MS (ESI): m/z (M+1) 439.1.

To a suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acidhydrochloride salt (230 mg, 0.92 mmol) in anhydrous acetonitrile (5 mL)was added 1 drop of DMF followed by (COCl)₂ (1.0 mL, 10.6 mmol). Theresulting mixture was stirred at room temperature for 1 hr. The solventwas evaporated. The freshly generated acid chloride was dissolved in dryDCM (2 mL) and then introduced to a solution of6-amino-9-(2-methyl-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(190) (200 mg, 0.46 mmol) in DCM (5 mL). Stirring was continued at roomtemperature for 1 hr before the reaction was quenched with MeOH (2 mL).The solvent was removed and the residue was pre-purified by columnchromatography (silica gel, 0 to 10% methanol in methylene chloride(0.3% Et₃N)) followed by preparative HPLC (RP, C18, 10 to 95%acetonitrile in water (0.2% NH₃.H₂O)) to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-4-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(191) (14 mg, 5%) as a white solid. LC-MS (ESI): m/z (M+1) 576.1. ¹H NMR(400 MHz, DMSO) δ 8.05 (s, 1H), 7.54-7.39 (m, 5H), 7.37-7.30 (m, 2H),7.23-7.10 (m, 5H), 6.72-6.60 (m, 1H), 6.06-5.93 (m, 1H), 5.87 (s, 2H),3.24 (s, 3H), 3.11 (d, J=6.2 Hz, 2H), 2.17 (s, 3H), 2.12 (s, 3H),1.63-1.55 (m, 1H), 0.36-0.29 (m, 2H), 0.25-0.19 (m, 2H).

Example 45 Synthesis of(E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(201)

To a solution of 2-methyl-5-nitroaniline (5 g, 32.86 mmol) in EtOH (60mL) was added (Boc)₂O (9.32 g, 42.72 mmol). The mixture was stirred atr.t. for 24 hrs. A yellow precipitate was collected by filtration, andwas further washed with petroleum ether to give tert-butyl2-methyl-5-nitrophenylcarbamate (192) (6.3 g, 76%) as yellow solid.LC-MS (ESI): m/z (M+1) 253.1.

To a stirred suspension of tert-butyl 2-methyl-5-nitrophenylcarbamate(192) (5 g, 19.8 mmol) and Cs₂CO₃ (12.9 g, 39.6 mmol) in DMF (80 mL) wasadded MeI (4.22 g, 29.7 mmol). The mixture was stirred at r.t. for 5 hrsunder N₂ atmosphere. The reaction was quenched with water (100 mL) andthe resulting mixture was extracted with EA (50 mL×3). The combinedorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo to give tert-butyl methyl(2-methyl-5-nitrophenyl)carbamate(193) (5.1 g, 97%) as yellow solid. LC-MS (ESI): m/z (M+1) 267.2.

In a similar manner as described in Example 44, tert-butyl5-amino-2-methylphenyl(methyl)carbamate (194) (2.66 g, 100%) wasprepared as a light yellow solid starting from tert-butylmethyl(2-methyl-5-nitrophenyl)carbamate (193) (3.0 g). LC-MS (ESI): m/z(M+1) 237.2.

In a similar manner as described in Example 44, tert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-methylphenyl(methyl)carbamate(195) (5.32 g, 85%) was prepared as a yellow solid starting fromtert-butyl 5-amino-2-methylphenyl(methyl)carbamate (194) (2.66 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1). LC-MS (ESI): m/z(M+1) 555.6.

In a similar manner as described in Example 44, tert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-methylphenyl(methyl)carbamate(196) (2.4 g, 85%) was prepared as a yellow solid starting fromtert-butyl5-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-2-methylphenyl(methyl)carbamate(195) (3 g). LC-MS (ESI): m/z (M+1) 525.1.

In a similar manner as described in Example 44, tert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(197) (2.3 g, 100%) was prepared as a yellow solid starting fromtert-butyl5-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-2-methylphenyl(methyl)carbamate(196) (2.2 g). LC-MS (ESI): m/z (M+1) 551.2.

In a similar manner as described in Example 44, tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(198) (1.33 g, 100%) was prepared as a light yellow solid starting fromtert-butyl5-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(197) (2.0 g). LC-MS (ESI): m/z (M+1) 371.2.

In a similar manner as described in Example 44, tert-butyl5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(199) (1.4 g, 70%) was prepared as a light yellow solid starting fromtert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(198) (1.3 g) and 4-phenoxyphenylboronic acid. LC-MS (ESI): m/z (M+1)539.1.

In a similar manner as described in Example 44,6-amino-9-(4-methyl-3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(200) (quant.) was prepared as a yellow solid starting from tert-butyl5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methylphenyl(methyl)carbamate(199) (1.4 g). LC-MS (ESI): m/z (M+1) 439.1.

In a similar manner as described in Example 44,(E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(201) (24 mg, 18%) was prepared as a white solid starting from6-amino-9-(4-methyl-3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(200) (100 mg). LC-MS (ESI): m/z (M+1) 576.1. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.71-7.33 (m, 8H), 7.21-7.12 (m, 5H), 6.77-6.68 (m, 1H),5.87 (s, 3H), 3.17 (s, 3H), 2.26-2.09 (m, 4H), 1.01-0.05 (m, 4H).

Example 46 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(211)

To a solution of 2-methoxy-5-nitroaniline (2.0 g, 13 mmol) in EtOH (30mL) was added Boc anhydride (8.6 g, 39 mmol). The resulting mixture wasstirred at rt for 24 hrs under N₂ atmosphere. The solvents were removedin vacuo. The residue was washed with petroleum ether, dried undervacuum to give tert-butyl 3-methyl-5-nitrophenylcarbamate (202) (3.3 g,quant.) as a yellow solid. LC-MS (ESI): m/z (M+1) 253.0.

In a similar manner as described in Example 44, tert-butylmethyl(3-methyl-5-nitrophenyl)carbamate (203) (3.5 g, 100%) was preparedas a brown solid starting from tert-butyl3-methyl-5-nitrophenylcarbamate (202) (3.3 g). LC-MS (ESI): m/z (M+1)267.2.

In a similar manner as described in Example 44, tert-butyl3-amino-5-methylphenyl(methyl)carbamate (204) (3.1 g, 99%) was preparedas a brown solid starting from tert-butylmethyl(3-methyl-5-nitrophenyl)carbamate (203) (3.5 g). LC-MS (ESI): m/z(M+1) 237.2.

In a similar manner as described in Example 44, tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methylphenyl(methyl)carbamate(205) (6.9 g, 94%) was prepared as a brown oil starting from tert-butyl3-amino-5-methylphenyl(methyl)carbamate (204) (3.1 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1). LC-MS (ESI): m/z(M+1) 555.1.

In a similar manner as described in Example 44, tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methylphenyl(methyl)carbamate(206) (6.0 g, 92%) was prepared as a brown solid starting fromtert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methylphenyl(methyl)carbamate(205) (6.9 g). LC-MS (ESI): m/z (M+1) 525.1.

In a similar manner as described in Example 44, tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(207) (5.1 g, 81%) was prepared as a brown oil starting from tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methylphenyl(methyl)carbamate(206) (6.0 g). LC-MS (ESI): m/z (M+1) 551.1.

In a similar manner as described in Example 44, tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(208) (807 mg, 100%) was prepared as a yellow solid starting fromtert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(207) (1.2 g). LC-MS (ESI): m/z (M+1) 371.2.

In a similar manner as described in Example 44, tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(209) (420 mg, 36%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(208) (807 mg) and 4-phenoxyphenylboronic acid (1.58 g). LC-MS (ESI):m/z (M+1) 539.1.

In a similar manner as described in Example 44,6-amino-9-(3-methyl-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(210) (293 mg, 86%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl(methyl)carbamate(209) (420 mg). LC-MS (ESI): m/z (M+1) 439.1.

In a similar manner as described in Example 44,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(211) (44 mg, 12%) was prepared as a white solid starting from6-amino-9-(3-methyl-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(210) (293 mg). LC-MS (ESI): m/z (M+1) 576.1. ¹H NMR (400 MHz, DMSO) δ8.26 (HCOOH), 8.11 (s, 1H), 7.53-7.32 (m, 6H), 7.23-7.09 (m, 6H),6.73-6.60 (m, 1H), 6.01 (d, J=15.4 Hz, 1H), 5.86 (s, 2H), 3.25 (s, 3H),3.12 (d, J=6.4 Hz, 2H), 2.38 (s, 3H), 2.12 (s, 3H), 1.65-1.55 (m, 1H),0.37-0.28 (m, 2H), 0.24-0.16 (m, 2H).

Example 47 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(224)

To a refluxing solution of 3-methoxy-5-nitrobenzoic acid (2.12 g, 10.7mmol) and K₂CO₃ (1.68 g, 12.2 mmol) in anhydrous acetone (20 mL) wasadded dimethyl sulfate (2 mL) dropwise over a period of 30 min. Thereaction mixture was refluxed overnight and cooled down to roomtemperature. The solvent was removed in vacuo. The resulting solid waswashed with water, dried in vacuo to give methyl3-methoxy-5-nitrobenzoate (212) (2.3 g, quant.) as a yellow solid. LC-MS(ESI): m/z (M+1) 212.1.

To a solution of methyl 3-methoxy-5-nitrobenzoate (212) (2.3 g, 11 mmol)in methanol (20 mL) was added aqueous ammonium hydroxide (25 mL). Themixture was stirred in a sealed tube at rt for 3 days, then concentratedin vacuo. The resulting solid was filtered, washed with water, dried invacuo to give 3-methoxy-5-nitrobenzamide (213) (2.1 g, quant.) as abrown solid. LC-MS (ESI): m/z (M+1) 197.1.

To a solution of NaOH (6 g, 150 mmol) in water (50 mL) at 0° C. wasadded neat bromine (4.8 g, 30 mmol) dropwise. A portion of this preparedaqueous NaOBr (21 mL) was slowly transferred to a solution of3-methoxy-5-nitrobenzamide (213) (2.0 g, 10 mmol) in methanol (60 mL).The stirring was continued for 1.5 hrs at room temperature. The solventwas removed under reduced pressure. The solid residue was redissolved ina solution of NaHCO₃ (1.2 g) in water (60 mL), heated to 80° C., andstirred for 2 hrs. The orange precipitate was collected by filtration toyield 3-methoxy-5-nitroaniline (214) (1.0 g, 59%). LC-MS (ESI): m/z(M+1) 169.0.

In a similar manner as described in Example 46, tert-butyl3-methoxy-5-nitrophenylcarbamate (215) (710 mg, 44%) was prepared as abrown solid starting from 3-methoxy-5-nitroaniline (214) (1.0 g). LC-MS(ESI): m/z (M+1) 269.1.

In a similar manner as described in Example 44, tert-butyl3-methoxy-5-nitrophenyl(methyl)carbamate (216) (733 mg, 100%) wasprepared as a brown solid starting from tert-butyl3-methoxy-5-nitrophenylcarbamate (215) (700 mg). LC-MS (ESI): m/z (M+1)283.2.

In a similar manner as described in Example 44, tert-butyl3-amino-5-methoxyphenyl(methyl)carbamate (217) (655 mg, 100%) wasprepared as a brown solid starting from tert-butyl3-methoxy-5-nitrophenyl(methyl)carbamate (216) (733 mg). LC-MS (ESI):m/z (M+1) 253.1.

In a similar manner as described in Example 44, tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methoxyphenyl(methyl)carbamate(218) (800 mg, 54%) was prepared as a brown oil starting from tert-butyl3-amino-5-methoxyphenyl(methyl)carbamate (217) (655 mg) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (922 mg). LC-MS(ESI): m/z (M+1) 571.1.

In a similar manner as described in Example 44, tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methoxyphenyl(methyl)carbamate(219) (750 mg, 100%) was prepared as a brown solid starting fromtert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methoxyphenyl(methyl)carbamate(218) (800 mg). LC-MS (ESI): m/z (M+1) 541.1.

In a similar manner as described in Example 44, tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(220) (540 mg, 68%) was prepared as a brown oil starting from tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methoxyphenyl(methyl)carbamate(219) (750 mg). LC-MS (ESI): m/z (M+1) 567.1.

In a similar manner as described in Example 44, tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(221) (300 mg, 82%) was prepared as a yellow solid starting fromtert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(220) (540 mg). LC-MS (ESI): m/z (M+1) 387.2.

In a similar manner as described in Example 44, tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(222) (230 mg, 54%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(221) (300 mg) and 4-phenoxyphenylboronic acid (500 mg). LC-MS (ESI):m/z (M+1) 555.1.

In a similar manner as described in Example 44,6-amino-9-(3-methoxy-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(223) (129 mg, 67%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl(methyl)carbamate(222) (230 mg). LC-MS (ESI): m/z (M+1) 455.1.

In a similar manner as described in Example 44,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(224) (69 mg, 12%) was prepared as a white solid starting from6-amino-9-(3-methoxy-5-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(223) (129 mg). LC-MS (ESI): m/z (M+1) 592.1. ¹H NMR (400 MHz, DMSO) δ8.27 (HCOOH), 8.11 (s, 1H), 7.51-7.39 (m, 4H), 7.27 (s, 1H), 7.21-7.11(m, 6H), 6.96 (s, 1H), 6.75-6.61 (m, 1H), 6.04 (d, J=15.2 Hz, 1H), 5.87(s, 2H), 3.80 (s, 3H), 3.26 (s, 3H), 3.13 (d, J=6.5 Hz, 2H), 2.12 (s,3H), 1.64-1.55 (m, 1H), 0.38-0.27 (m, 2H), 0.25-0.16 (m, 2H).

Example 48 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methylamino)but-2-enamidehydrochloride (229)

To a suspension of methanamine (33% in MeOH, 20 mL, 56 mmol) and K₂CO₃(11 g, 80 mmol) in THF (50 mL) at 0° C. was added (E)-methyl4-bromobut-2-enoate (5 g, 28 mmol). After the resulting mixture wasstirred at 0° C. for 3 hrs, the reaction solution was filtered. Thefiltrate was concentrated in vacuo and the residue was dissolved in DCM(50 mL), Et₃N (7.7 mL, 56 mmol) and (Boc)₂O (7.32 g, 33.6 mmol) wereadded. The resulting mixture was stirred at r.t. for 2 hrs before water(50 mL) was introduced. The layers were separated and the aqueous phasewas extracted with DCM (20 mL×2). The combined organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography (silica gel, 0 to 50 ethyl acetate inpetroleum ether) to give (E)-methyl4-(tert-butoxycarbonyl(methyl)amino)but-2-enoate (225) (3 g, two stepsyield 47%) as a yellow oil. LC-MS (ESI): m/z (M+1) 230.1.

To a solution of (E)-methyl4-(tert-butoxycarbonyl(methyl)amino)but-2-enoate (225) (6.1 g, 26.6mmol) in THF (60 mL) at 0° C. and under N₂ atmosphere was added asolution of lithium hydroxide monohydrate (1.68 g, 43.6 mmol) in water(20 mL) dropwise over 15 min. The resulting mixture was stirred at 0° C.for 3 hrs. Cold water (150 mL) and petroleum ether (200 mL) were thenintroduced and the stirring was continued at 0° C. for 10 min. Thelayers were separated. The aqueous layer was carefully acidified withcon. HCl at 0° C. to pH˜4 and was extracted with DCM (80 mL×3). Thecombined organic extracts were dried over Na₂SO₄, filtered andevaporated under reduced pressure to give(E)-4-(tert-butoxycarbonyl(methyl)amino)but-2-enoic acid (226) (3.5 g,61% yield) as a yellow oil. LC-MS (ESI): m/z (M−1) 214.1.

To a suspension of (E)-4-(tert-butoxycarbonyl(methyl)amino)but-2-enoicacid (226, 200 mg, 0.93 mmol) in anhydrous DCM (3 mL) at 0° C. was added1 drop of DMF, followed by addition of (COCl)₂ (0.4 mL, 0.93 mmol). Theresulting mixture was stirred at room temperature for 1 hr. The solventwas then evaporated. The freshly generated acid chloride (227) wasdissolved in anhydrous DCM (2 mL) and was subsequently introduced into asolution of6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (197 mg, 0.465 mmol) in DCM (3 mL). After the reaction mixture wasstirred at room temperature for 1 hr, the reaction was quenched withMeOH (2 mL). Solvents were removed and the residue was purified bypreparative TLC (DCM/MeOH=8/1 (v/v)) to give (E)-tert-butyl4-((3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)(methyl)amino)-4-oxobut-2-enyl(methyl)carbamate(228) (120 mg, 42% yield) as a white solid. LC-MS (ESI): m/z (M+1)622.1.

To a solution of (E)-tert-butyl4-((3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)(methyl)amino)-4-oxobut-2-enyl(methyl)carbamate(228) (100 mg, 0.16 mmol) in MeCN (2 mL) at 0° C. was added HCl (con.0.3 mL). The mixture was stirred at 0° C. for 1 hour, the solvent wasremoved in vacuo and dried by lypholization to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methylamino)but-2-enamide(229) (75 mg, 89% yield) as a white solid. LC-MS (ESI): m/z (M+1) 522.0.¹H NMR (400 MHz, DMSO) δ 9.20 (br, 2H), 8.33 (s, 1H), 7.69-7.57 (m, 3H),7.51 (d, J=8.8 Hz, 2H), 7.46-7.38 (m, 3H), 7.23-7.11 (m, 5H), 6.74-6.64(m, 1H), 6.36-6.16 (m, 1H), 3.60 (d, J=5.7 Hz, 2H), 3.31 (s, 3H),2.44-2.35 (m, 3H).

Example 49 Synthesis of(E)-N-(3-(6-amino-7-(4-(benzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(234)

To a suspension of 4-bromophenol (3.7 g, 21.4 mmol) and K₂CO₃ (4 g, 29.1mmol) in MeCN (40 mL) was added (bromomethyl)benzene (3.66 g, 21.4mmol). The resulting mixture was stirred at r.t. overnight. The solidwas filtered off, and the filtrate was concentrated in vacuo to givecrude 1-(benzyloxy)-4-bromobenzene (230) (5.2 g, 92% yield) as a yellowoil.

To a stirred solution of 1-(benzyloxy)-4-bromobenzene (230) (1.5 g, 6mmol) in anhydrous THF (20 mL) at −78° C. and under N₂ atmosphere wasadded n-BuLi (2.5 M, 3.1 mL, 7.8 mmol) via syringe over 5 min. Stirringwas continued for 20 min at the same temperature before triisopropylborate (1.5 mL) was introduced. The reaction was then slowly warmed upto r.t. over a 3-hrs period, and was quenched with IN HCl (5 mL). Thelayers were separated. The aqueous layer was extracted with ethylacetate (30 mL×2). The combined organic layers were washed with brine,dried over MgSO₄. and evaporated. The residue was washed with PE andEt₂O to give 4-(benzyloxy)phenylboronic acid (231) (1 g, 73%) as whitesolid. LC-MS (ESI): m/z (M−1) 227.1.

To a mixture of tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (500 mg,1.4 mmol) and 4 A MS (500 mg) in anhydrous DMF (15 mL) were added4-(benzyloxy)phenylboronic acid (231) (800 mg, 3.5 mmol), Cu(OAc)₂ (255mg, 1.4 mmol) and pyridine (670 mg, 8.4 mmol). The reaction mixture washeated to 40° C. overnight under O₂ atmosphere. After the reaction wascompleted, the oil bath was removed. The reaction was then cooled downto r.t. and was quenched with NH₃.H₂O (3 mL). The solvent was evaporatedin vacuum. The residue was purified by column chromatography (silicagel, 0 to 50% ethyl acetate in petroleum ether) to give tert-butyl3-(6-amino-7-(4-(benzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(232) (365 mg, 48%) as a yellow solid. LC-MS (ESI): m/z (M+1) 539.2.

To a solution of tert-butyl3-(6-amino-7-(4-(benzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(232) (365 mg, 0.678 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise.The resulting mixture was stirred at rt for 1 hr before concentrated.The residue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to afford6-amino-7-(4-(benzyloxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(233) (quant.) as a yellow oil. LC-MS (ESI): m/z (M+1) 439.2.

In a similar manner as described in Example 48,(E)-N-(3-(6-amino-7-(4-(benzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(234) (50 mg, 38%) was prepared as a white solid starting from6-amino-7-(4-(benzyloxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(233) (100 mg). LC-MS (ESI): m/z (M+1) 576.2. ¹H NMR (400 MHz, DMSO) δ8.10 (s, 1H), 7.71-7.55 (m, 3H), 7.49-7.38 (m, 6H), 7.37-7.30 (m, 2H),7.20 (d, J=8.9 Hz, 2H), 6.68 (dt, J=15.1, 6.5 Hz, 1H), 6.00 (d, J=14.1Hz, 1H), 5.68 (br, 2H), 5.17 (s, 2H), 3.27 (s, 3H), 3.12 (d, J=5.6 Hz,2H), 2.12 (s, 3H), 1.67-1.52 (m, 1H), 0.36-0.29 (m, 2H), 0.25-0.16 (m,2H).

Example 50 Synthesis of(E)-N-(3-(6-amino-7-(4-(3-methylbenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(239)

In a similar manner as described in Example 49,1-((4-bromophenoxy)methyl)-3-methylbenzene (235) (3.2 g, 100%) wasprepared as a yellow oil starting from 4-bromophenol (2 g) and1-(bromomethyl)-3-methyl benzene (2.14 g).

In a similar manner as described in Example 49,4-(3-methylbenzyloxy)phenylboronic acid (236) (1.1 g, 100%) was preparedas a white solid starting from1-((4-bromophenoxy)methyl)-3-methylbenzene (235) (1.5 g). LC-MS (ESI):m/z (M−1) 241.1.

In a similar manner as described in Example 49, tert-butyl3-(6-amino-7-(4-(3-methylbenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(237) (370 mg, 48%) was prepared as a yellow solid starting from3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate (24) (500mg) and 4-(3-methylbenzyloxy)phenylboronic acid (236) (850 mg). LC-MS(ESI): m/z (M−1) 553.2.

In a similar manner as described in Example 49,6-amino-9-(3-(methylamino)phenyl)-7-(4-(3-methylbenzyloxy)phenyl)-7H-purin-8(9H)-one(238) (100 mg, 100%) was prepared as a yellow solid starting fromtert-butyl3-(6-amino-7-(4-(3-methylbenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(237) (120 mg). LC-MS (ESI): m/z (M−1) 453.2.

In a similar manner as described in Example 48,(E)-N-(3-(6-amino-7-(4-(3-methylbenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(239) (50 mg, 39%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-(3-methylbenzyloxy)phenyl)-7H-purin-8(9H)-one(238) (100 mg). LC-MS (ESI): m/z (M+1) 590.2. ¹H NMR (400 MHz, DMSO) δ8.10 (s, 1H), 7.72-7.54 (m, 3H), 7.45 (d, J=8.9 Hz, 2H), 7.37-7.23 (m,4H), 7.21-7.11 (m, 3H), 6.74-6.62 (m, 1H), 6.08-5.89 (m, 1H), 5.68 (br,2H), 5.13 (s, 2H), 3.27 (s, 3H), 3.12 (d, J=5.9 Hz, 2H), 2.32 (s, 3H),2.12 (s, 3H), 1.64-1.54 (m, 1H), 0.35-0.29 (m, 2H), 0.24-0.16 (m, 2H).

Example 51 Synthesis of(E)-N-(3-(6-amino-7-(4-(3-fluorobenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(244)

In a similar manner as described in Example 49,1-((4-bromophenoxy)methyl)-3-fluorobenzene (240) (3.2 g, 100%) wasprepared as a yellow oil starting from 4-bromophenol (2 g) and1-(bromomethyl)-3-fluorobenzene (2.2 g).

In a similar manner as described in Example 49,4-(3-fluorobenzyloxy)phenylboronic acid (241) (400 mg, 31%) was preparedas a light yellow oil starting from1-((4-bromophenoxy)methyl)-3-fluorobenzene (240) (1.5 g). LC-MS (ESI):m/z (M−1) 245.1.

In a similar manner as described in Example 49, tert-butyl3-(6-amino-7-(4-(3-fluorobenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(242) (300 mg, 39%) was prepared as a yellow solid starting from3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl) carbamate (24) (500mg) and 4-(3-fluorobenzyloxy)phenylboronic acid (241) (400 mg). LC-MS(ESI): m/z (M−1) 557.2.

In a similar manner as described in Example 49,6-amino-9-(3-(fluoroamino)phenyl)-7-(4-(3-methylbenzyloxy)phenyl)-7H-purin-8(9H)-one(243) (100 mg, 100%) was prepared as a yellow solid starting fromtert-butyl3-(6-amino-7-(4-(3-fluorobenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(242) (120 mg). LC-MS (ESI): m/z (M−1) 457.2.

In a similar manner as described in Example 48,(E)-N-(3-(6-amino-7-(4-(3-fluorobenzyloxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(244) (50 mg, 38%) was prepared as a white solid starting from6-amino-9-(3-(fluoroamino)phenyl)-7-(4-(3-methylbenzyloxy)phenyl)-7H-purin-8(9H)-one(243) (100 mg). LC-MS (ESI): m/z (M+1) 594.1. ¹H NMR (400 MHz, DMSO) δ8.10 (s, 1H), 7.68-7.56 (m, 3H), 7.51-7.41 (m, 3H), 7.35-7.28 (m, 3H),7.23-7.12 (m, 3H), 6.73-6.63 (m, 1H), 6.08-5.92 (m, 1H), 5.69 (s, 2H),5.20 (s, 2H), 3.27 (s, 3H), 3.11 (d, J=6.4 Hz, 2H), 2.11 (s, 3H),1.63-1.56 (m, 1H), 0.35-0.29 (m, 2H), 0.23-0.16 (m, 2H).

Example 52 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-3-(pyridin-2-yl)acrylamide(247)

A solution of pyridine-2-carbaldehyde (5.0 g, 46.7 mmol), malonic acid(4.8 g, 46.1 mmol), pyridine (10 mL) and piperidine (0.05 mL) was heatedat 100° C. for 2 hrs followed by stirring at r.t. for 10 hrs. Thereaction mixture was then acidified to pH˜4 with 6N HCl. The generatedprecipitate was collected by filtration. After washed with cold waterand dried over pump, (E)-3-(pyridin-2-yl)acrylic acid (245) was obtainedas a white solid (2.3 g, 35%). LC-MS (ESI): m/z (M+1) 150.2.

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-3-(pyridin-2-yl)acrylamide(247) (52 mg, 20%) was prepared as a light yellow oil starting from(E)-3-(pyridin-2-yl)acrylic acid (140 mg) and6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (200 mg). LC-MS (ESI): m/z (M−1) 556.1. ¹H NMR (400 MHz, DMSO) δ8.53 (d, J=4.4 Hz, 1H), 8.04 (s, 1H), 7.87-7.78 (m, 1H), 7.75-7.68 (m,2H), 7.66-7.54 (m, 3H), 7.50 (d, J=8.8 Hz, 2H), 7.45-7.38 (m, 3H),7.36-7.30 (m, 1H), 7.22-7.10 (m, 5H), 7.07-6.96 (m, 1H), 5.91 (br, 2H),3.35 (s, 3H).

Example 53 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(255)

To a solution of tert-butyl 3-methyl-5-nitrophenylcarbamate (202) (1.47g, 5.8 mmol) in THF/MeOH/H₂O (24 mL/12 mL/6 mL) were added iron powder(3.28 g, 58 mmol) and NH₄Cl (6.32 g, 117 mmol). The resulting mixturewas heated at 50° C. for 5 hrs under N₂. After cooling down to r.t., thereaction mixture was filtered through a pad of Celite. The filtrate wasextracted with EtOAc (50 mL×3), and the combined organic extract waswashed with water and brine, dried over Na₂SO₄, and concentrated invacuo to give tert-butyl 3-amino-5-methylphenylcarbamate (248) (0.9 g,75%) as a brown solid. LC-MS (ESI): m/z (M+1) 223.1.

To a solution of tert-butyl 3-amino-5-methylphenylcarbamate (248) (0.9g, 4.0 mmol) and TEA (1.1 mL, 8 mmol) in dioxane (30 mL) was addedN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (1.4 g, 4.0 mmol).The resulting mixture was heated at 70° C. overnight under N₂ beforecooled down to rt, quenched with water (50 mL) and extracted with EtOAc(50 mL×3). The combined organic extracts was washed with brine, driedover Na₂SO₄, and concentrated in vacuo. The crude product was purifiedby column chromatography (silica gel, 0 to 20% ethyl acetate inpetroleum ether) to give tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methylphenylcarbamate(249) (1.8 g, 82%) as a brown oil. LC-MS (ESI): m/z (M+1) 541.1.

To a solution of tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methylphenylcarbamate(249) (1.8 g, 3.3 mmol) in THF/MeOH/H₂O (24 mL/12 mL/6 mL) were addediron powder (1.87 g, 33 mmol) and NH₄Cl (3.6 g, 67 mmol). The resultingsuspension was heated at 50° C. for 5 hrs under N₂. After cooled down tort, the reaction mixture was filtered through a pad of Celite. Thefiltrate was extracted with EtOAc (50 mL×3), and the combined organicextracts was washed with water and brine, dried over Na₂SO₄, andconcentrated in vacuo. tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methylphenylcarbamate(250) (1.56 g, 92%) was obtained as a brown oil. LC-MS (ESI): m/z (M−1)511.0.

To a stirred solution of tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methylphenylcarbamate(250) (1.56 g, 3.0 mmol) and TEA (0.85 mL, 6.1 mmol) in anhydrous DCM(20 mL) at 0° C. and under N₂ atmosphere was added a solution oftriphosgene (456 mg, 1.5 mmol) in anhydrous DCM (10 mL) dropwise over 1hr. The stirring was continued for 1 hr before quenched with water (100mL). The layers were separated. The organic layer was washed with waterand brine, dried over Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified by column chromatography (silica gel, 0 to 30%ethyl acetate in petroleum ether) to give tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(251) (1.6 g, quant.) as a brown solid. LC-MS (ESI): m/z (M+1) 537.1.

To a mixture of tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(251) (1.6 g, 3.0 mmol) in MeOH (30 mL) was added Pd(OH)₂/C (1.6 g, 20wt %) and 3 drops of con. HCl. The resulting mixture was purged with H₂(2×) before heated to 60° C. overnight under H₂ atmosphere. The mixturewas cooled down to rt, and filtered through a Celite pad. The filtratewas concentrated in vacuo to give tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate (252) (1.04g, 97%) as a yellow solid. LC-MS (ESI): m/z (M+1) 357.0.

In a similar manner as described in Example 46, tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(253) (350 mg, 46%) was prepared from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate (252) (520mg) and 4-phenoxyphenylboronic acid (938 mg). LC-MS (ESI): m/z (M+1)525.1.

In a similar manner as described in Example 46,6-amino-9-(3-amino-5-methylphenyl-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(254) (230 mg, 81%) was prepared from tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(253) (350 mg). LC-MS (ESI): m/z (M+1) 425.1.

To a suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acidhydrochloride salt (207 mg, 1.1 mmol) in anhydrous acetonitrile (5 mL)was added 1 drop of DMF followed by addition of (COCl)₂ (1.0 mL, 10.6mmol). The resulting mixture was stirred at room temperature for 1 hr.The solvent was evaporated. The freshly generated acid chloride wasdissolved in dry DCM (2 mL) and was then introduced to a solution of6-amino-9-(3-amino-5-methylphenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(254) (230 mg, 0.54 mmol) in DCM (5 mL). Stirring was continued at roomtemperature for 1 hr before quenched with MeOH (2 mL). The solvent wasremoved and the residue was pre-purified by column chromatography(silica gel, 0 to 10% methanol in methylene chloride (0.3% Et₃N))followed by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water(0.2% NH₃.H₂O)) to give(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(255) (45 mg, 15%) as a white solid. LC-MS (ESI): m/z (M+1) 562.1. ¹HNMR (400 MHz, DMSO) δ 10.18 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H),7.56-7.47 (m, 3H), 7.43 (t, J=7.9 Hz, 2H), 7.24-7.07 (m, 6H), 6.81-6.70(m, 1H), 6.22 (d, J=15.3 Hz, 1H), 5.81 (s, 2H), 3.29-3.25 (m, 2H), 2.33(s, 3H), 2.25 (s, 3H), 1.77-1.68 (m, 1H), 0.46-0.38 (m, 2H), 0.34-0.27(m, 2H).

Example 54 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(263)

In a similar manner as described in Example 53, tert-butyl3-amino-5-methoxyphenylcarbamate (256) (2.19 g, 97%) was prepared as abrown solid starting from tert-butyl 3-methoxy-5-nitrophenylcarbamate(215) (2.54 g). LC-MS (ESI): m/z (M+1) 239.0.

In a similar manner as described in Example 53, tert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methoxyphenylcarbamate(257) (3.35 g, 65%) was prepared as a brown oil starting from tert-butyl3-amino-5-methoxyphenylcarbamate (256) (2.19 g) andN,N-dibenzyl-6-chloro-5-nitropyrimidin-4-amine (1) (3.3 g). LC-MS (ESI):m/z (M+1) 557.1.

In a similar manner as described in Example 53, tert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methoxyphenylcarbamate(258) (750 mg, 100%) was prepared as a brown solid starting fromtert-butyl3-(6-(dibenzylamino)-5-nitropyrimidin-4-ylamino)-5-methoxyphenylcarbamate(257) (800 mg). LC-MS (ESI): m/z (M+1) 527.1.

In a similar manner as described in Example 53, tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(259) (1.2 g, 37%) was prepared as a brown solid starting fromtert-butyl3-(5-amino-6-(dibenzylamino)pyrimidin-4-ylamino)-5-methoxyphenylcarbamate(258) (3.12 g). LC-MS (ESI): m/z (M+1) 553.1.

In a similar manner as described in Example 53, tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate (260) (787mg, 97%) was prepared as a yellow solid starting from tert-butyl3-(6-(dibenzylamino)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(259) (1.2 g). LC-MS (ESI): m/z (M+1) 373.2.

In a similar manner as described in Example 53, tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(261) (236 mg, 54%) was prepared as a brown oil starting from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate (260) (300mg) and 4-phenoxyphenylboronic acid (600 mg). LC-MS (ESI): m/z (M+1)541.1.

In a similar manner as described in Example 53,6-amino-9-(3-amino-5-methoxyphenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(262) (192 mg, 100%) was prepared as a brown oil starting fromtert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(261) (236 mg). LC-MS (ESI): m/z (M+1) 441.1.

In a similar manner as described in Example 53,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(263) (54 mg, 21%) was prepared as a white solid starting from6-amino-9-(3-amino-5-methoxyphenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(262) (192 mg). LC-MS (ESI): m/z (M+1) 577.8. ¹H NMR (400 MHz, DMSO) δ10.23 (s, 1H), 8.10 (s, 1H), 7.59-7.48 (m, 3H), 7.47-7.37 (m, 3H),7.25-7.07 (m, 5H), 6.96-6.89 (m, 1H), 6.82-6.71 (m, 1H), 6.22 (d, J=15.4Hz, 1H), 5.82 (s, 2H), 3.76 (s, 3H), 3.28 (d, J=6.2 Hz, 2H), 2.25 (s,3H), 1.79-1.66 (m, 1H), 0.46-0.39 (m, 2H), 0.34-0.28 (m, 2H).

Example 55 Synthesis of(E)-N-(3-(6-amino-7-(4-(4-hydroxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(269)

To a mixture of 4-bromophenol (760 mg, 4.4 mmol) and 4 A MS (500 mg) indry DCM (20 mL) was added 4-methoxyphenylboronic acid (1.0 g, 6.6 mmol),Cu(OAc)₂ (798 mg, 4.4 mmol) and pyridine (2.1 mL, 26 mmol). The reactionmixture was heated at 37° C. overnight under O₂ atmosphere, thenfiltered through a Celite pad. The filtrate was diluted with water (80mL), extracted with DCM (50 mL×3). The combined organic extracts waswashed with water and brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by column chromatography (silica gel, 0 to 10%ethyl acetate in methylene chloride) to give1-bromo-4-(4-methoxyphenoxy)benzene (264) (1.2 g, quant.) as a yellowsolid. LC-MS (ESI): m/z (M/M−2) 278.9/276.9.

To a stirred solution of 1-bromo-4-(4-methoxyphenoxy)benzene (264) (1.2g, 4.3 mmol) in anhydrous THF (20 mL) at −78° C. and under N₂ atmospherewas added n-butyllithium (2.2 mL, 5.6 mmol, 2.5 M in hexane) dropwiseover 30 min. The resulting mixture was continued for 1 hr at −78° C.before triisopropyl borate (2.0 mL, 8.6 mmol) was introduced. Stirringwas continued for additional 1 hr. The reaction was then allowed toslowly warm up to r.t., quenched with IN HCl (30 mL) and concentrateddown to half a volume in vacuo. The resulting mixture was extracted withEtOAc (50 mL×3). The combined organic extracts was washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The crude product waswashed with petroleum ether, dried under vacuum to give4-(4-methoxyphenoxy)phenylboronic acid (265) (1.05 g, quant.) as a whitesolid. LC-MS (ESI): m/z (M−1) 243.0.

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(4-(4-methoxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (266) (320 mg, 38%) was prepared from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (535 mg,1.5 mmol) and 4-(4-methoxyphenoxy)phenylboronic acid (265) (1.05 g).LC-MS (ESI): m/z (M+1) 555.1.

In a similar manner as described in Example 5,6-amino-7-(4-(4-methoxyphenoxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(267) (223 mg, 85%) was prepared from tert-butyl3-(6-amino-7-(4-(4-methoxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (266) (320 mg). LC-MS (ESI): m/z (M+1) 455.1.

In a similar manner as described in Example 53,(E)-N-(3-(6-amino-7-(4-(4-methoxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(268) (230 mg, 79%) was prepared as a yellow solid starting from6-amino-7-(4-(4-methoxyphenoxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(267) (223 mg). LC-MS (ESI): m/z (M+1) 592.1.

To a stirred solution of(E)-N-(3-(6-amino-7-(4-(4-methoxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(268) (230 mg, 0.39 mmol) in anhydrous DCM (8 mL) at −78° C. and underN₂ atmosphere was added BBr₃ (0.19 mL, 2.0 mmol) dropwise. The resultingmixture was stirred for 1 hr at −78° C. before allowed to slowly warm upto rt., quenched with ice-water, and basified with sodium carbonatesolution to pH 6-7. The solution was concentrated in vacuo, and theresidue was purified by preparative HPLC (RP, C18, 10 to 95%acetonitrile in water (0.2% NH₃.H₂O)) to give(E)-N-(3-(6-amino-7-(4-(4-hydroxyphenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(269) (32 mg, 14%) as a white solid. LC-MS (ESI): m/z (M+1) 578.1.

¹H NMR (400 MHz, DMSO) δ 8.23 (s, 1H), 8.10 (s, 1H), 7.70-7.53 (m, 3H),7.44 (d, J=8.8 Hz, 2H), 7.33 (d, J=7.7 Hz, 1H), 7.10-6.91 (m, 4H), 6.80(d, J=8.9 Hz, 2H), 6.74-6.60 (m, 1H), 6.07-5.91 (m, 1H), 5.78 (s, 2H),3.27 (s, 3H), 3.11 (d, J=6.4 Hz, 2H), 2.11 (s, 3H), 1.64-1.54 (m, 1H),0.37-0.25 (m, 2H), 0.25-0.14 (m, 2H).

Example 56 Synthesis of(E)-N-(4-(6-amino-9-(3-(4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamido)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)benzamide(274)

To a stirred solution of 4-bromoaniline (4.7 g, 27 mmol) and TEA (3.8mL, 27 mmol) in anhydrous DCM (30 mL) at 0° C. and under N₂ atmospherewas added benzoyl chloride (3.8 mL, 33 mmol) dropwise. Stirring wascontinued for 1 hr at rt before quenched with MeOH (10 mL). Theresulting mixture was concentrated in vacuo. The crude product waswashed with ether and water, dried in vacuo to giveN-(4-bromophenyl)benzamide (270) (7.0 g, 93%) as a white solid. LC-MS(ESI): m/z (M/M+2) 276.0/278.0.

In a similar manner as described in Example 55, 4-benzamidophenylboronicacid (271) (0.73 g, 42%) was prepared as a yellow solid fromN-(4-bromophenyl)benzamide (270) (2.0 g). LC-MS (ESI): m/z (M+1) 242.1.

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(4-benzamidophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(272) (227 mg, 73%) was prepared from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (200 mg)and 4-benzamidophenylboronic acid (271) (406 mg). LC-MS (ESI): m/z (M+1)552.1.

In a similar manner as described in Example 5,N-(4-(6-amino-9-(3-(methylamino)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)benzamide(273) (186 mg, 100%) was prepared from tert-butyl3-(6-amino-7-(4-benzamidophenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(272) (227 mg). LC-MS (ESI): m/z (M+1) 452.1.

In a similar manner as described in Example 53,(E)-N-(4-(6-amino-9-(3-(4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamido)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)benzamide(274) (85 mg, 35%) was prepared as a white solid starting fromN-(4-(6-amino-9-(3-(methylamino)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)phenyl)benzamide(273) (186 mg). LC-MS (ESI): m/z (M+1) 589.1. ¹H NMR (400 MHz, DMSO) δ10.49 (s, 1H), 8.12 (s, 1H), 8.03-7.93 (m, 4H), 7.68 (d, J=8.8 Hz, 1H),7.64-7.45 (m, 7H), 7.39-7.29 (m, 1H), 6.78-6.57 (m, 1H), 6.01 (d, J=14.9Hz, 1H), 5.77 (s, 2H), 3.28 (s, 3H), 3.12 (d, J=6.2 Hz, 2H), 2.12 (s,3H), 1.66-1.53 (m, 1H), 0.36-0.29 (m, 2H), 0.24-0.18 (m, 2H).

Example 57 Synthesis of(E)-4-(6-amino-9-(3-(4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamido)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)-N-phenylbenzamide(280)

A suspension of 4-bromobenzoic acid (4.02 g, 20 mmol) in SOCl₂ (40 mL)was heated to reflux for 1 hr. Excess SOCl₂ was removed under reducedpressure and the residue was diluted with DCM (10 mL) before it wasintroduced into a solution of aniline (1.86 g, 20 mmol) and TEA (1 mL)in DCM (10 mL) at 0° C. under N₂ atmosphere. The resulting mixture wasstirred at r.t. overnight and was next quenched with IN NaOH (30 mL).The layers were separated and the organic layer was washed with IN HCl(30 mL), H₂O, dried over Na₂SO₄ and concentrated to provide4-bromo-N-phenylbenzamide (275) (4.47 g, 81%) as a white solid. LC-MS(ESI): m/z (M/M+2) 274.0/276.0.

A suspension of 4-bromo-N-phenylbenzamide (4.47 g, 16.188 mmol),4-bromo-N-phenylbenzamide (4.11 g, 16.188 mmol), Pd(dppf)Cl₂.DCM (397mg, 0.486 mmol) and KOAc (4.766 g, 48.564 mmol) in dioxane (100 mL) waspurged with N₂ (3×). The reaction mixture was then stirred at 90° C.overnight. The solvents were evaporated and the residue was directlypurified by flash chromatography (silica gel, 0 to 10% EA in PE/DCM(1/1)) to affordN-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (276)(5.4 g, 100%) as a yellow solid. LC-MS (ESI): m/z (M+1) 324.1.

To a solution ofN-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.94g, 6 mmol) in THF/H₂O (40 mL/8 mL) was added NaIO₄ (7.70 g, 36 mmol).The resulting mixture was stirred at r.t. overnight before diluted withEA (30 mL) and H₂O (30 mL). The product was extracted with 85% DCM/IPA(100 mL). The organic extract was dried over Na₂SO₄. Filtered andconcentrated. The residue was purified by flash chromatography (silicagel, 0 to 50% EA in PE) to provide 4-(phenylcarbamoyl)phenylboronic acid(277) (816 mg, 56%). LC-MS (ESI): m/z (M−1) 240.0.

In a similar manner as described in Example 7, tert-butyl3-(6-amino-8-oxo-7-(4-(phenylcarbamoyl)phenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (278) (225 mg, 41%) was prepared as a yellow oil fromtert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(24) (356 mg) and 4-(phenylcarbamoyl)phenylboronic acid (241 mg). LC-MS(ESI): m/z (M+1) 551.8.

In a similar manner as described in Example 7,(E)-4-(6-amino-9-(3-(4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamido)phenyl)-8-oxo-8,9-dihydro-7H-purin-7-yl)-N-phenylbenzamide(280) (75 mg, 37%) was prepared as a white solid in two steps startingfrom tert-butyl3-(6-amino-8-oxo-7-(4-(phenylcarbamoyl)phenyl)-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (278) (225 mg). LC-MS (ESI): m/z (M+1) 589.1. ¹H NMR(400 MHz, DMSO) δ 10.37 (s, 1H), 9.52 (br, 1H), 8.21-8.11 (m, 3H), 7.79(d, J=8.2 Hz, 2H), 7.71 (d, J=8.4 Hz, 1H), 7.67-7.58 (m, 4H), 7.43-7.32(m, 3H), 7.11 (t, J=7.4 Hz, 1H), 6.70 (dt, J=14.9, 7.4 Hz, 1H),6.48-6.24 (m, 1H), 6.03 (s, 2H), 3.94 (s, 2H), 3.32 (s, 3H), 2.75 (s,4H), 0.94-0.64 (m, 4H).

Example 58 Synthesis of(E)-N-(3-(6-amino-7-(3-methoxy-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(285)

In a similar manner as described in Example 40,4-bromo-2-methoxy-1-phenoxybenzene (281) (1.6 g, 78%) was prepared from4-bromo-2-methoxyphenol (1.5 g).

In a similar manner as described in Example 40,3-methoxy-4-phenoxyphenylboronic acid (282) (488 mg, 56%) was preparedfrom 4-bromo-2-methoxy-1-phenoxybenzene (281) (1.0 g). LC-MS (ESI): m/z(M+1) 243.1.

In a similar manner as described in Example 40, tert-butyl3-(6-amino-7-(3-methoxy-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(283) (342 mg, 44%) was prepared from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (500 mg)and 3-methoxy-4-phenoxyphenylboronic acid (282) (488 mg). LC-MS (ESI):m/z (M+1) 555.2.

In a similar manner as described in Example 40,6-amino-7-(3-methoxy-4-phenoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(284) (quant.) was prepared from tert-butyl3-(6-amino-7-(3-methoxy-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(283) (170 mg). LC-MS (ESI): m/z (M+1) 455.2.

In a similar manner as described in Example 40,(E)-N-(3-(6-amino-7-(3-methoxy-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(285) (118 mg, 66%) was prepared as a white solid starting from6-amino-7-(3-methoxy-4-phenoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(284) (136 mg). LC-MS (ESI): m/z (M+1) 592.3. ¹H NMR (400 MHz, DMSO) δ8.12 (s, 1H), 7.73-7.53 (m, 3H), 7.33 (dd, J=14.1, 5.4 Hz, 4H), 7.15 (d,J=8.4 Hz, 1H), 7.10-7.03 (m, 2H), 6.99 (d, J=7.7 Hz, 2H), 6.73-6.63 (m,1H), 6.06-5.92 (m, 3H), 3.76 (s, 3H), 3.28 (s, 3H), 3.12 (d, J=5.9 Hz,2H), 2.12 (s, 3H), 1.64-1.55 (m, 1H), 0.35-0.28 (m, 2H), 0.24-0.17 (m,2H).

Example 59 Synthesis of(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(290)

In a similar manner as described in Example 55,1-bromo-2-methyl-4-phenoxybenzene (286) (8.0 g, 95%) was prepared as ayellow liquid from 4-bromo-3-methylphenol (6.0 g) and phenylboronic acid(11.7 g).

In a similar manner as described in Example 55,2-methyl-4-phenoxyphenylboronic acid (287) (3.0 g, 87%) was prepared asa white solid from 1-bromo-2-methyl-4-phenoxybenzene (286) (4.0 g).LC-MS (ESI): m/z (M−1) 226.0.

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (288) (350 mg, 52%) was prepared as a brown oil fromtert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(24) (450 mg) and 2-methyl-4-phenoxyphenylboronic acid (287) (861 mg).LC-MS (ESI): m/z (M+1) 539.1.

In a similar manner as described in Example 5,6-amino-7-(2-methyl-4-phenoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(289) (195 mg, 68%) was prepared as a brown oil from tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (288) (350 mg). LC-MS (ESI): m/z (M+1) 439.1.

In a similar manner as described in Example 53,(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(290) (18 mg, 7%) was prepared as a white solid starting from6-amino-7-(2-methyl-4-phenoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(289) (195 mg). LC-MS (ESI): m/z (M+1) 576.1. ¹H NMR (400 MHz, DMSO) δ9.46 (s, 1H), 8.13 (s, 1H), 7.80-7.53 (m, 3H), 7.46-7.37 (m, 3H),7.24-7.11 (m, 3H), 7.08 (d, J=2.6 Hz, 1H), 6.96 (dd, J=8.5, 2.8 Hz, 1H),6.74-6.63 (m, 1H), 6.39-6.23 (m, 1H), 5.72 (s, 2H), 4.02-3.85 (m, 2H),3.31 (s, 3H), 2.84-2.64 (m, 4H), 2.16 (s, 3H), 0.91-0.64 (m, 4H).

Example 60 Synthesis of(E)-N-(3-(6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(295)

In a similar manner as described in Example 49,1-(benzyloxy)-4-bromo-2-methoxybenzene (291) (1.44 g, quant.) wasprepared from 4-bromo-2-methoxyphenol (1 g) and (bromomethyl)benzene(0.93 g).

In a similar manner as described in Example 49,4-(benzyloxy)-3-methoxyphenylboronic acid (292) (410 mg, 59%) wasprepared from 1-(benzyloxy)-4-bromo-2-methoxybenzene (291) (800 mg).LC-MS (ESI): m/z (M−1) 257.1.

In a similar manner as described in Example 7, tert-butyl3-(6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (293) (324 mg, 37%) was prepared from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (24) (550 mg)and 4-(benzyloxy)-3-methoxyphenylboronic acid (292) (400 mg). LC-MS(ESI): m/z (M+1) 569.3.

In a similar manner as described in Example 49,6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(294) (quant.) was prepared from tert-butyl3-(6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (293) (170 mg). LC-MS (ESI): m/z (M+1) 469.3.

In a similar manner as described in Example 7,(E)-N-(3-(6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(295) (53 mg, 29%) was prepared from6-amino-7-(4-(benzyloxy)-3-methoxyphenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(294) (140 mg). LC-MS (ESI): m/z (M+1) 606.3. ¹H NMR (400 MHz, DMSO) δ8.10 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.62-7.57 (m, 2H), 7.47 (d, J=7.3Hz, 2H), 7.40 (t, J=7.4 Hz, 2H), 7.33 (d, J=5.1 Hz, 2H), 7.19 (dd,J=9.9, 5.4 Hz, 2H), 7.05 (dd, J=8.5, 2.3 Hz, 1H), 6.68 (dd, J=14.2, 7.6Hz, 1H), 6.13-5.92 (m, 1H), 5.73 (br, 2H), 5.15 (s, 2H), 3.78 (s, 3H),3.27 (s, 3H), 3.11 (d, J=6.0 Hz, 2H), 2.12 (s, 3H), 1.68-1.53 (m, 1H),0.36-0.15 (m, 4H).

Example 61 Synthesis of(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(298)

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(296) (245 mg, 31%) was prepared as a brown oil from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate (251) (520mg) and 2-methyl-4-phenoxyphenylboronic acid (287) (995 mg). LC-MS(ESI): m/z (M+1) 539.1.

In a similar manner as described in Example 5,6-amino-9-(3-amino-5-methylphenyl)-7-(2-methyl-4-phenoxyphenyl)-7H-purin-8(9H)-one(297) (199 mg, quant.) was prepared as a brown oil from tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenylcarbamate(296) (245 mg). LC-MS (ESI): m/z (M+1) 439.1.

In a similar manner as described in Example 53,(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methylphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(298) (17 mg, 6%) was prepared as a white solid from6-amino-9-(3-amino-5-methylphenyl)-7-(2-methyl-4-phenoxyphenyl)-7H-purin-8(9H)-one(297) (199 mg). LC-MS (ESI): m/z (M+1) 576.1. ¹H NMR (400 MHz, DMSO) δ10.18 (s, 1H), 8.09 (s, 1H), 7.77 (s, 1H), 7.53 (s, 1H), 7.49-7.36 (m,3H), 7.24-7.10 (m, 4H), 7.07 (d, J=2.5 Hz, 1H), 6.97-6.90 (m, 1H),6.81-6.70 (m, 1H), 6.22 (d, J=15.2 Hz, 1H), 5.62 (s, 2H), 3.28-3.26 (m,2H), 2.34 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 1.75-1.68 (m, 1H),0.47-0.37 (m, 2H), 0.36-0.25 (m, 2H).

Example 62 Synthesis of(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(301)

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(299) (359 mg, 50%) was prepared as a brown oil from tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate (251) (487mg) and 2-methyl-4-phenoxyphenylboronic acid (287) (895 mg). LC-MS(ESI): m/z (M+1) 555.1.

In a similar manner as described in Example 5,6-amino-9-(3-amino-5-methoxyphenyl)-7-(2-methyl-4-phenoxyphenyl)-7H-purin-8(9H)-one(300) (243 mg, 83%) was prepared as a brown oil from tert-butyl3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenylcarbamate(299) (359 mg). LC-MS (ESI): m/z (M+1) 455.1.

In a similar manner as described in Example 53,(E)-N-(3-(6-amino-7-(2-methyl-4-phenoxyphenyl)-8-oxo-7H-purin-9(8H)-yl)-5-methoxyphenyl)-4-(cyclopropyl(methyl)amino)but-2-enamide(301) (35 mg, 6%) was prepared as a white solid from6-amino-9-(3-amino-5-methylphenyl)-7-(2-methyl-4-phenoxyphenyl)-7H-purin-8(9H)-one(300) (243 mg). LC-MS (ESI): m/z (M+1) 593.2. ¹H NMR (400 MHz, DMSO) δ10.23 (s, 1H), 8.10 (s, 1H), 7.57-7.50 (m, 1H), 7.48-7.39 (m, 4H),7.24-7.11 (m, 3H), 7.07 (d, J=2.6 Hz, 1H), 6.98-6.89 (m, 2H), 6.83-6.70(m, 1H), 6.21 (d, J=15.4 Hz, 1H), 5.63 (s, 2H), 3.76 (s, 3H), 3.28 (d,J=6.2 Hz, 2H), 2.25 (s, 3H), 2.16 (s, 3H), 1.77-1.68 (m, 1H), 0.45-0.39(m, 2H), 0.34-0.28 (m, 2H).

Example 63 Synthesis of(E)-6-amino-9-(4-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(306)

In a similar manner as described in Example 55,1-(4-bromophenoxy)-3-fluorobenzene (302) (2.5 g, 96%) was prepared as ayellow solid from 4-bromophenol (1.7 g) and 3-fluorophenylboronic acid(1.95 g). LC-MS (ESI): m/z (M+1) 267.1.

In a similar manner as described in Example 55,4-(3-fluorophenoxy)phenylboronic acid (303) (1.7 g, 78%) was prepared asa yellow solid from 1-(4-bromophenoxy)-3-fluorobenzene (302) (2.5 g).LC-MS (ESI): m/z (M+1) 231.0.

In a similar manner as described in Example 5, tert-butyl6-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(304) (317 mg, 57%) was prepared as a brown oil from tert-butyl6-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(158) (372 mg) and 4-(3-fluorophenoxy)phenylboronic acid (303) (340 mg).LC-MS (ESI): m/z (M+1) 571.0.

In a similar manner as described in Example 5,6-amino-9-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(305) (261 mg, quant.) was prepared as a brown oil from tert-butyl6-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(304) (317 mg). LC-MS (ESI): m/z (M+1) 470.9.

In a similar manner as described in Example 5,(E)-6-amino-9-(4-(4-(cyclopropyl(methyl)amino)but-2-enoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(306) (72 mg, 21%) was prepared as a white solid starting from6-amino-9-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(305) (261 mg). LC-MS (ESI): m/z (M+1) 607.6. ¹H NMR (400 MHz, DMSO) δ8.11 (s, 1H), 7.55-7.37 (m, 3H), 7.32 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.8Hz, 2H), 7.10-6.92 (m, 4H), 6.84-6.67 (m, 2H), 5.93 (s, 2H), 4.39-4.25(m, 2H), 4.04-3.87 (m, 2H), 2.48 (s, 3H, overlapped with DMSO),2.38-1.99 (m, 3H), 0.60-0.01 (m, 4H).

Example 64 Synthesis of(S,E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(309)

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (307) (353 mg, 51%) was prepared as a brown oil fromtert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate(24) (459 mg) and 4-(3-fluorophenoxy)phenylboronic acid (303) (300 mg).LC-MS (ESI): m/z (M+1) 543.2.

In a similar manner as described in Example 5,6-amino-7-(4-(3-fluorophenoxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(308) (quant.) was prepared as a brown oil from tert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl(methyl)carbamate (307) (118 mg). LC-MS (ESI): m/z (M+1) 443.2.

In a similar manner as described in Example 5,(S,E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(309) (13 mg, 9%) was prepared as a white solid starting from6-amino-7-(4-(3-fluorophenoxy)phenyl)-9-(3-(methylamino)phenyl)-7H-purin-8(9H)-one(308) (97 mg) and (S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoicacid (81 mg) (121). LC-MS (ESI): m/z (M+1) 610.1. ¹H NMR (400 MHz, DMSO)δ 8.11 (s, 1H), 7.69-7.40 (m, 6H), 7.34 (d, J=8.0 Hz, 1H), 7.22 (d,J=7.8 Hz, 2H), 7.08-6.92 (m, 3H), 6.71-6.59 (m, 1H), 6.12-5.99 (m, 1H),5.94 (s, 2H), 3.73-3.64 (m, 1H), 3.62-3.46 (m, 2H), 3.41-3.33 (m, 1H),3.27 (s, 3H), 3.11-2.88 (m, 3H), 2.00 (s, 3H), 1.90-1.72 (m, 1H),1.70-1.50 (m, 1H).

Example 65 Synthesis of(E)-N-(5-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(312)

In a similar manner as described in Example 5, tert-butyl5-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(310) (263 mg, 36%) was prepared as a brown oil from tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl) carbamate(168) (500 mg) and 4-(3-fluorophenoxy)phenylboronic acid (303) (500 mg).LC-MS (ESI): m/z (M+1) 573.1.

In a similar manner as described in Example 5,6-amino-7-(4-(3-fluorophenoxy)phenyl)-9-(4-methoxy-3-(methylamino)phenyl)-7H-purin-8(9H)-one(311) (217 mg, quant.) was prepared as a brown oil from tert-butyl5-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate(310) (263 mg). LC-MS (ESI): m/z (M+1) 473.1.

In a similar manner as described in Example 5,(E)-N-(5-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide(312) (29 mg, 10%) was prepared as a white solid starting from6-amino-7-(4-(3-fluorophenoxy)phenyl)-9-(4-methoxy-3-(methylamino)phenyl)-7H-purin-8(9H)-one(311) (217 mg) and (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acidhydrochloride salt (176 mg). LC-MS (ESI): m/z (M+1) 610.1. ¹H NMR (400MHz, DMSO) δ 8.09 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.59-7.37 (m, 4H),7.30 (d, J=9.1 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 7.10-6.91 (m, 3H),6.70-6.56 (m, 1H), 5.91 (s, 2H), 5.81 (d, J=15.1 Hz, 1H), 3.83 (s, 3H),3.12 (s, 3H), 3.07 (d, J=6.5 Hz, 2H), 2.10 (s, 3H), 1.64-1.50 (m, 1H),0.31 (d, J=4.9 Hz, 2H), 0.24-0.14 (m, 2H).

Example 66 Synthesis of(S,E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(313)

In a similar manner as described in Example 5,(S,E)-N-(5-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)-2-methoxyphenyl)-N-methyl-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(313) (8 mg, 3%) was prepared as a white solid starting from6-amino-9-(4-methoxy-3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(170) (200 mg) and(S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (195 mg)(121). LC-MS (ESI): m/z (M+1) 622.1. ¹H NMR (400 MHz, DMSO) δ 8.09 (s,1H), 7.69-7.61 (m, 1H), 7.57-7.52 (m, 1H), 7.51-7.38 (m, 4H), 7.30 (d,J=8.9 Hz, 1H), 7.19 (d, J=7.4 Hz, 1H), 7.17-7.11 (m, 4H), 6.67-6.54 (m,1H), 5.90-5.75 (m, 3H), 3.83 (s, 3H), 3.75-3.64 (m, 1H), 3.62-3.43 (m,2H), 3.42-3.31 (m, 1H), 3.12 (s, 3H), 3.04-2.84 (m, 3H), 1.98 (s, 3H),1.86-1.73 (m, 1H), 1.70-1.51 (m, 1H).

Example 67 Synthesis of(S,E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(316)

In a similar manner as described in Example 5, tert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate(314) (650 mg, 65%) was prepared as a light yellow solid from tert-butyl5-(6-amino-8-oxo-7H-purin-9(8H)-yl)-2-methoxyphenyl(methyl)carbamate (5)(650 mg) and 4-(3-fluorophenoxy)phenylboronic acid (303) (880 mg). LC-MS(ESI): m/z (M+1) 529.2.

In a similar manner as described in Example 5,6-amino-9-(3-aminophenyl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(315) (quant.) was prepared as a yellow oil from tert-butyl3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate(314) (650 mg). LC-MS (ESI): m/z (M+1) 429.2.

In a similar manner as described in Example 5,(S,E)-N-(3-(6-amino-7-(4-(3-fluorophenoxy)phenyl)-8-oxo-7H-purin-9(8H)-yl)phenyl)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(316) (21 mg, 15%) was prepared as a white solid starting from6-amino-9-(3-aminophenyl)-7-(4-(3-fluorophenoxy)phenyl)-7H-purin-8(9H)-one(315) (100 mg) and(S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid (51 mg)(121). LC-MS (ESI): m/z (M+1) 596.1. ¹H NMR (400 MHz, DMSO) δ 10.28 (s,1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.55 (d, J=8.6Hz, 2H), 7.48-7.40 (m, 2H), 7.31 (d, J=7.7 Hz, 1H), 7.22 (d, J=8.6 Hz,2H), 7.15-6.88 (m, 3H), 6.79-6.72 (m, 1H), 6.29 (d, J=15.7 Hz, 1H),3.82-3.70 (m, 2H), 3.65-3.56 (m, 1H), 3.52-3.45 (m, 1H), 3.18-3.08 (m,3H), 2.14 (s, 3H), 2.01-1.90 (m, 1H), 1.78-1.67 (m, 1H).

Example 68 Synthesis of(S,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(317)

In a similar manner as described in Example 5,(S,E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enamide(317) (10 mg, 7%) was prepared as a white solid starting from6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7)(100 mg) and (S,E)-4-(methyl(tetrahydrofuran-3-yl)amino)but-2-enoic acid(67 mg) (121). LC-MS (ESI): m/z (M+1) 578.1. ¹H NMR (400 MHz, DMSO) δ10.26 (s, 1H), 8.09 (s, 1H), 8.00 (s, 1H), 7.71-7.61 (m, 1H), 7.56-7.35(m, 5H), 7.34-7.25 (m, 1H), 7.23-7.02 (m, 5H), 6.79-6.70 (m, 1H), 6.28(d, J=16.1 Hz, 1H), 5.80 (s, 2H), 3.87-3.67 (m, 2H), 3.66-3.55 (m, 1H),3.54-3.42 (m, 1H), 3.20-3.05 (m, 3H), 2.14 (s, 3H), 2.02-1.87 (m, 1H),1.81-1.65 (m, 1H).

Example 69 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide(318)

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-((2-methoxyethyl)(methyl)amino)but-2-enamide(318) (36 mg, 27%) was prepared as a white solid starting from6-amino-9-(3-aminophenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one (7)(100 mg) and (E)-4-((2-methoxyethyl)(methyl)amino)but-2-enoic acid (62mg). LC-MS (ESI): m/z (M+1) 566.1. ¹H NMR (400 MHz, DMSO) δ 10.29 (s,1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.55-7.38 (m,5H), 7.31 (d, J=8.8 Hz, 1H), 7.23-7.08 (m, 5H), 6.74 (dt, J=15.4, 6.0Hz, 1H), 6.29 (d, J=15.3 Hz, 1H), 5.82 (br, 2H), 3.44 (t, J=5.7 Hz, 2H),3.27-3.13 (m, 5H), 2.64-2.53 (m, 2H), 2.32-2.17 (m, 3H).

Example 70 Synthesis of(R,E)-2-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile(324)

To a solution of cyclopropanecarbaldehyde (4 g, 57 mmol) in EtOH (50 mL)were added tert-butyl 2-cyanoacetate (319) (8.04 g, 57 mmol) andpiperidine (628 mg, 7.4 mmol). The resulting mixture was stirred at 85°C. for 2 hrs under N₂ atmosphere. The solvents were removed under vacuumand the residue was purified by flash chromatography (silica gel, 0 to5% EA in PE) to provide (E)-tert-butyl 2-cyano-3-cyclopropylacrylate(320) (7.7 g, 100%).

To a solution of (E)-tert-butyl 2-cyano-3-cyclopropylacrylate (320) (7.7g, 40 mmol) in DCM (30 mL) was added TFA (30 mL). The resulting mixturewas stirred at r.t. overnight. Excess TFA was removed under vacuum. Theresidue was triturated with H₂O/MeOH (10:1, 10 mL×3). The white solidwas collected by filtration and dried to provide(E)-2-cyano-3-cyclopropylacrylic acid (321) (3.7 g, 68%). LC-MS (ESI):m/z (M−1) 136.0.

To a mixture of (R)-tert-butyl3-(6-amino-8-oxo-7H-purin-9(8H)-yl)piperidine-1-carboxylate (87) (200mg, 0.6 mmol) and 4 A MS (300 mg) in dry DMF (8 mL) were added4-phenoxyphenylboronic acid (384 mg, 1.8 mmol), Cu(OAc)₂ (110 mg, 0.6mmol) and pyridine (284 μL, 3.6 mmol). The reaction mixture was heatedat 37° C. for 5 h under an O₂ atmosphere, and filtered through a Celitepad. The filtrate was diluted with water (30 mL) and extracted withEtOAc (10 mL×3). The combined organic layer was washed with water andbrine, dried over Na₂SO₄, and concentrated. The residue was purified bycolumn chromatography (silica gel, 0 to 5% methanol in methylenechloride) to give (R)-tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine-1-carboxylateas a brown solid (322) (297 mg, 99.0%). LC-MS (ESI): m/z (M+1) 503.

To a solution of (R)-tert-butyl3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine-1-carboxylate(322) (297 mg, 0.6 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise.The reaction mixture was stirred at r.t. for 1 h and then concentrated.The residue was purified by column chromatography (silica gel, 0 to 5%methanol in methylene chloride (0.3% Et₃N)) to give(R)-6-amino-7-(4-phenoxyphenyl)-9-(piperidin-3-yl)-7H-purin-8(9H)-one asa yellow solid (323) (227 mg, 95.4%). LC-MS (ESI): m/z (M+1) 403.

In a similar manner as described in Example 21,(R,E)-2-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)piperidine-1-carbonyl)-3-cyclopropylacrylonitrile(324) (13 mg, 11% yield) was prepared as a white solid starting from(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine(323) (95 mg) and (E)-2-cyano-3-cyclopropylacrylic acid (321) (49 mg).LC-MS (ESI): m/z (M+1) 522.1. ¹H NMR (400 MHz, DMSO) δ 8.12 (s, 1H),7.50-7.35 (m, 4H), 7.26-7.04 (m, 5H), 6.70-6.55 (m, 1H), 5.77 (s, 2H),4.64-3.39 (m, 4H), 2.70-2.51 (m, 1H), 2.02-1.46 (m, 5H), 1.19-1.09 (m,2H), 0.97-0.85 (m, 2H).

Example 71 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-2-cyano-3-cyclopropyl-N-methylacrylamide(325)

In a similar manner as described in Example 5,(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-2-cyano-3-cyclopropyl-N-methylacrylamide(325) (29 mg, 15%) was prepared as a white solid starting from6-amino-9-(3-(methylamino)phenyl)-7-(4-phenoxyphenyl)-7H-purin-8(9H)-one(32) (150 mg) and (E)-2-cyano-3-cyclopropylacrylic acid (86 mg) (121).LC-MS (ESI): m/z (M+1) 544.0. ¹H NMR (400 MHz, DMSO) δ 8.12 (s, 1H),7.80-7.55 (m, 3H), 7.53-7.30 (m, 5H), 7.25-7.02 (m, 5H), 6.55 (d, J=11.2Hz, 1H), 5.89 (br, 2H), 3.34 (s, 3H), 1.82-1.62 (m, 1H), 1.13-1.03 (m,2H), 0.80-0.68 (m, 2H).

Example 72 Synthesis of(E)-4-amino-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methylbut-2-enamide(326)

(E)-4-amino-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methylbut-2-enamide(326) was prepared in a similar manner as described in the proceduresabove. LC-MS (ESI): m/z (M+1) 508.1.

Example 73 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)acrylamide(327)

(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-N-methyl-3-(1-methyl-1H-imidazol-4-yl)acrylamide(327) was prepared in a similar manner as described in the proceduresabove. LC-MS (ESI): m/z (M+1) 559.1.

Example 74 Synthesis of(E)-N-((1s,4s)-4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)cyclohexyl)-4-(dimethylamino)-N-methylbut-2-enamide(328)

(E)-N-((1s,4s)-4-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)cyclohexyl)-4-(dimethylamino)-N-methylbut-2-enamide(328) was prepared in a similar manner as described in the proceduresabove. LC-MS (ESI): m/z (M+1) 542.1.

Example 75 Synthesis of(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(methylamino)but-2-enamide(329)

(E)-N-(3-(6-amino-8-oxo-7-(4-phenoxyphenyl)-7H-purin-9(8H)-yl)phenyl)-4-(methylamino)but-2-enamide(329) was prepared in a similar manner as described in the proceduresabove. LC-MS (ESI): m/z (M+1) 508.1.

Example 76a Btk In Vitro Inhibitory Activity (Method A) TR-FRET Assay

The Btk IC₅₀s of compounds disclosed herein is determined in both acellular kinase assay and in a cellular functional assay of BCR-inducedcalcium flux as described below.

Btk kinase activity is determined using a time-resolved fluorescenceresonance energy transfer (TR-FRET) methodology. Measurements areperformed in a reaction volume of 50 μL using 96-well assay plates.Kinase enzyme, inhibitor, ATP (at the K_(m) for the kinase), and 1 μMpeptide substrate (Biotin-AVLESEEELYSSARQ-NH₂) are incubated in areaction buffer composed of 20 mM Tris, 50 mM NaCl, MgCl₂ (5-25 mMdepending on the kinase), MnCl₂ (0-10 mM), 1 mM DTT, 0.1 mM EDTA, 0.01%bovine serum albumin, 0.005% Tween-20, and 10% DMSO at pH 7.4 for onehour. The reaction is quenched by the addition of 1.2 equivalents ofEDTA (relative to divalent cation) in 25 μL of 1× Lance buffer(Perkin-Elmer). Streptavidin-APC (Perkin-Elmer) and Eu-labeled p-Tyr100antibody (Perkin-Elmer) in 1× Lance buffer are added in a 25 μL volumeto give final concentrations of 100 nM and 2.5 nM, respectively, and themixture is allowed to incubate for one hour. The TR-FRET signal ismeasured on a multimode plate reader with an excitation wavelength(λ_(Ex)) of 330 nm and detection wavelengths (λ_(Em)) of 615 and 665 nm.Activity is determined by the ratio of the fluorescence at 665 nm tothat at 615 nm. For each compound, enzyme activity is measured atvarious concentrations of compound. Negative control reactions areperformed in the absence of inhibitor in replicates of six, and twono-enzyme controls are used to determine baseline fluorescence levels.Inhibition constants, K_(i)(app), were obtained using the programBatchK_(i) (Kuzmic et al. (2000), Anal. Biochem. 286:45-50). IC₅₀s areobtained according to the equation:

IC ₅₀ ={Ki(app)/(1+[ATP]/K _(m) ^(ATP))}+[E] _(total)/2;

For all kinases, [ATP]=K_(m) ^(ATP), [Btk]_(total)=0.5 nM and[Lck]_(total)=6 nM.

Example 76b Btk In Vitro Inhibitory Activity (Method B)

Kinase activity is measured in vitro using electrophoretic mobilityshift assay. The kinase reactions are assembled in a total volume of 25μL in 384 well plates. The reactions comprise: BTK enzyme (1 nM,N-terminal His6-tagged, recombinant, full-length, human BTK purifiedfrom baculovirus Sf21 insect cell system), inhibitor, ATP (16 μM, theapparent K_(m) for the kinase), fluorescently labeled peptide substrate(1 μM, FAM-GEEPLYWSFPAKKK-NH2) in a reaction buffer composed of 100 mMHEPES, pH7.5, 5 mM MgCl₂ 1 mM DTT, 0.1% bovine serum albumin, 0.01%Triton X-100, and 1% DMSO. The reaction is incubated for one hour and isquenched by the addition of 45 μL of termination buffer (100 mM HEPES,pH7.5, 0.01% Triton X-100, 30 mM EDTA). The terminated reactions areanalyzed using 12 channel LabChip® 3000 microfluidic detectioninstrument (Caliper Life Sciences). The enzymatic phosphorylation of thepeptide results in a change in net charge, enabling electrophoreticseparation of product from substrate peptide. As substrate and productpeptides are separated, two peaks of fluorescence are observed. Changein the relative fluorescence intensity of the substrate and productpeaks is the parameter measured, reflecting enzyme activity. In thepresence of an inhibitor, the ratio between product and substrate isaltered: the signal of the product decreases, while the signal of thesubstrate increases.

Activity in each sample is determined as the product to sum ratio (PSR):P/(S+P), where P is the peak height of the product peptide and S is thepeak height of the substrate peptide. For each compound, enzyme activityis measured at various concentrations (12 concentrations of compoundspaced by 3× dilution intervals). Negative control samples(0%—inhibition in the absence of inhibitor) and positive control samples(100%-inhibition, in the presence of 20 mM EDTA) are assembled inreplicates of four and are used to calculate %-inhibition values foreach inhibitor at each concentration. Percent inhibition (P_(inh)) isdetermined using following equation:

P _(inh)=(PSR _(0%) −PSR _(inh))/(PSR _(0%) −PSR _(100%))*100,

where PSR_(inh) is the product sum ratio in the presence of inhibitor,PSR_(0%) is the average product sum ration in the absence of inhibitorand PSR_(100%) is the average product sum ratio in 100%-inhibitioncontrol samples;

The IC50 values of inhibitors are determined by 4 parameter sigmoidaldose-response model fitting of the inhibition curves (P_(inh) versusinhibitor concentration) using XLfit 4 software.

Example 76c Btk In Vitro Inhibitory Activity (Method C)

Human Btk kinase (Genbank accession # NP_000052) was purified frominsect cells as a full-length construct containing a N-terminal 6×-Histag. Btk kinase activity was determined using a radiometric filterbinding assay. Measurements are performed in a low μL reaction volume384-well assay plates. BTK enzyme (8 nM final in reaction), inhibitor(at requested doses), and 0.2 mg/mL peptide substrate (Poly-Glu-Tyr, 4:1ratio) are incubated in a reaction buffer composed of 20 mM Hepes (pH7.5), 10 mM MgCl₂, 1 mM EGTA, 0.02% Brij35, 0.02 mg/ml BSA, 0.1 mMNa₃VO₄, 2 mM DTT, 1% DMSO for 15 min. followed by addition of 1 μM ATPto start the assay. Kinase reactions are carried out for 120 min. at RT.The reaction was stopped by spotting of reaction sample onto P81cationic exchange paper (Whatman). Unbound phosphate was removed byextensive washing of filters in 0.75% Phosphoric acid. After subtractionof background derived from control reactions containing inactive enzyme(via addition of saturating EDTA), kinase activity data for each dose ofcompound tested was expressed as the percent of remaining kinaseactivity in test samples compared to vehicle (dimethyl sulfoxide)reactions. IC₅₀ values and curve fits were obtained using Prism(GraphPad Software).

The degree of inhibition of a panel of kinases is determined using oneof the methods outlined in Example 76a, 76b and 76c.

BTK EGFR LCK Compound IC50 IC50 IC50 8 A A B 9 A A B 10 A A B 11 A A A14 A C C 17 A C C 27 A D D 30 A D D 33 A B C 34 A B C 35 A — — 43 A C B44 A C B 45 A C B 48 B D C 49 B D C 50 B D C 51 A B C 54 A C C 55 A C C63 A C B 64 A C B 67 B D C 75 A C B 76 A 77 A 78 A 81 A D C 82 A 90 A 93A 104 B D D 112 A C C 116 A 118 A B B 123 A C C 129 A C C 134 A B C 147A D D 151 A C C 161 A B C 171 A C C 181 B 191 B D D 201 A C C 211 A B C224 A C C 229 A A C 234 A C C 239 A C D 244 A C D 247 B C C 255 A B B263 A 269 A 274 A 280 B 285 A C C 290 A C C 295 A D D 298 A B C 301 A BC 306 A B C 309 A C C 312 A D D 313 A C C 316 A B C 317 A B B 318 A A B324 A B B 325 A B B 326 B 327 B C C 328 A A A 329 A A B IC₅₀: A <100 nM;100 nM ≦ B ≦ 1 μM; 1 μM < C ≦ 10 μM; D >10 μM; — = no data

Example 77a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is dissolved in DMSO and then mixed with 10 mL of 0.9%sterile saline. The mixture is incorporated into a dosage unit formsuitable for administration by injection.

Example 77b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is mixed with 750 mg of starch. The mixture isincorporated into an oral dosage unit for, such as a hard gelatincapsule, which is suitable for oral administration.

Example 77c Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I), (Ia), (Ib), (II),(IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc), with 420 mg of powderedsugar mixed, with 1.6 mL of light corn syrup, 2.4 mL distilled water,and 0.42 mL mint extract. The mixture is gently blended and poured intoa mold to form a lozenge suitable for buccal administration.

Example 77d Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III),(IIIa), (IIIb), or (IIIc) is mixed with 50 mg of anhydrous citric acidand 100 mL of 0.9% sodium chloride solution. The mixture is incorporatedinto an inhalation delivery unit, such as a nebulizer, which is suitablefor inhalation administration.

Example 77e Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is mixed with 2.5 g of methylcelluose (1500 mPa), 100mg of methylparapen, 5 g of glycerin and 100 mL of purified water. Theresulting gel mixture is then incorporated into rectal delivery units,such as syringes, which are suitable for rectal administration.

Example 77f Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is mixed with 1.75 g of hydroxypropyl celluose, 10 mLof propylene glycol, 10 mL of isopropyl myristate and 100 mL of purifiedalcohol USP. The resulting gel mixture is then incorporated intocontainers, such as tubes, which are suitable for topicaladministration.

Example 77g Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa),(IIIb), or (IIIc) is mixed with 0.9 g of NaCl in 100 mL of purifiedwater and filtered using a 0.2 micron filter. The resulting isotonicsolution is then incorporated into ophthalmic delivery units, such aseye drop containers, which are suitable for ophthalmic administration.

Example 78 Clinical Trial of a Compound of Formula (I), (Ia), (Ib),(II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) and CombinationChemotherapy in Treating Older Patients with Previously Untreated B-CellLymphoma

The purpose of this study is to determine how well giving a compound ofFormula (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or(IIIc) together with combination chemotherapy works in treating olderpatients with previously untreated B cell lymphoma.

Criteria

Disease Characteristics:

-   -   Histological diagnosis of aggressive B-cell lymphoma    -   Previously untreated disease    -   Stage I-IV disease    -   CD20-positive disease    -   Any International Prognostic Index (IPI) score    -   No secondary lymphoma after prior chemotherapy or radiotherapy    -   No primary CNS lymphoma    -   No primary gastrointestinal (MALT) lymphoma

Patient Characteristics:

-   -   ECOG performance status 0-2    -   Life expectancy≧3 months    -   AST and ALT≦3 times normal unless related to lymphoma    -   Bilirubin≦2 mg/dL unless related to lymphoma    -   Creatinine≦2 times normal unless related to lymphoma    -   Fertile patients must use effective contraception    -   No known allergic reactions against foreign proteins    -   No active infections requiring systemically administered        antibiotics or antiviral medications    -   No noncompensated heart failure    -   No dilatative cardiomyopathy    -   No coronary heart disease with ST-segment depression in ECG    -   No myocardial infarction during the past 6 months    -   No chronic lung disease with hypoxemia    -   No severe noncompensated hypertension    -   No severe noncompensated diabetes mellitus    -   No clinical signs of cerebral dysfunction    -   No severe psychiatric disease    -   No known HIV infection    -   No active chronic hepatitis B or C infection    -   No other concurrent diseases that exclude the administration of        therapy as outlined by the study protocol    -   More than 12 weeks since prior clinical trial participation    -   No prior participation in this study    -   No prior therapy, including murine antibody, for this cancer    -   No prior organ transplantation    -   No concurrent response-adapted radiotherapy (“iceberg        radiotherapy”)    -   No other concurrent anticancer chemotherapy or other study        medication

Study Design Ages Eligible for Study: 61 Years to 80 Years GendersEligible for Study: Both Accepts Healthy Volunteers: No

All patients undergo the following treatment.

-   -   Prephase treatment: Patients receive vincristine subcutaneously        on day −6 and oral prednisone on days −6 to 0.    -   Immunochemotherapy and radiotherapy: Patients receive CHOP        chemotherapy comprising cyclophosphamide IV over 15 minutes,        doxorubicin hydrochloride IV, and vincristine IV on day 1 and        oral prednisone once daily on days 1-5. Patients also receive        pegfilgrastim subcutaneously on days 4, 18, and 32. Treatment        with CHOP chemotherapy repeats every 14 days for up to 6 courses        in the absence of disease progression or unacceptable toxicity.        Patients who show no response after course 4 of CHOP        chemotherapy proceed to salvage chemotherapy off study.    -   Patients are evaluated 2-4 weeks after completion of CHOP.        Patients with initial bulky disease (i.e., diameter ≧7.5 cm) or        extranodal involvement AND achieving complete remission (CR),        unconfirmed CR (CRu), or partial remission undergo radiotherapy        5 days a week for 4 weeks. Patients who do not achieve CR or CRu        2 months after completion of radiotherapy proceed to salvage        chemotherapy off study.    -   Patients are then stratified according to center, International        Prognostic Index (1-2 vs 3-5), disease involvement (bulky vs        extranodal vs bulky and/or extranodal), age (61-70 years old vs        71-80 years old), and gender. Patients are randomized to 1 of 2        treatment arms.    -   Arm I: Patients receive compound of Formula (I), (Ia), (Ib),        (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) at 500 mg        once daily for 105 days.    -   Arm II (pharmacokinetic-based dose of compound of Formula (I),        (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), or        (IIIc)) at 500 mg once daily for 35 days.    -   Some patients undergo blood sample collection periodically        during and after treatment for pharmacokinetic studies.    -   After completion of study treatment, patients are followed every        3 months for 2 years, every 6 months for 3 years, and then once        a year thereafter.

Primary Outcome Measures

-   -   Pharmacokinetics (in first 20 patients of each cohort with a        distinct variation of the compound of Formula (I), (Ia), (Ib),        (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IIIc) schedule)    -   Safety and treatment related deaths at 3 months after study        completion    -   Toxicity assessed by NCI criteria, adverse events, serious        adverse events, protocol adherence, and treatment-related deaths        at 3 months after study completion

Secondary Outcome Measures

-   -   Time to treatment failure assessed at 2 years within the study        and periodically thereafter    -   Complete response rate assessed at 2 years within the study and        periodically thereafter    -   Progression rate    -   Survival time    -   Progression-free survival

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound of Formula (I) having the structure:

wherein: L_(a) is a bond, —CH₂—, —CH(OH)—, —C(O)—, —CH₂O—, —OCH₂—, —SCH₂, —CH₂S—, —N(R₂₁)—, —N(R₂₁)C(O)—, —C(O)N(R₂₁)—, —N(R₂₁)C(O)N(R₂₁)—, —O—, —S—, —S(O)—, —S(O)₂—, —N(R₂₁)S(O)₂—, or —S(O)₂N(R₂₁)—; Ar is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; R₃ is optionally substituted C₃-C₆ alkyl, substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —(C═O)C₁-C₆ alkyl, —(C═O)OR₄, —(C═O)NR₄R₄, —(C═O)SR₄, -G-X, or

G is optionally substituted aryl, or optionally substituted heteroaryl; X is optionally substituted cycloalkyl; optionally substituted heterocycloalkyl; optionally substituted aryl, optionally substituted heteroaryl, —OR₄, —SR₄, or —NR₄R₄; each R₄ is each independently H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, C₃-C₆ cycloalkyl, or C₂-C₆ heterocycloalkyl; Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, aryl, and heteroaryl; Z is C(═O), OC(═O), N(R₂₁)C(═O), C(═S), S(═O)_(x), OS(═O)_(x), or N(R₂₁)S(═O)_(x), where x is 1 or 2; each R₂₄ is each independently halogen, —CN, —NO₂, —OH, —OCF₃, —OCH₂F, —OCF₂H, —CF₃, —SR₂₁, —N(R₂₁)S(═O)₂R₂₃, —S(═O)₂N(R₂₁)(R₂₂), —S(═O)R₂₃, —S(═O)₂R₂₃, —C(═O)R₂₃, —OC(═O)R₂₃, —CO₂R₂₁, —N(R₂₁)(R₂₂), —C(═O)N(R₂₁)(R₂₂), —N(R₂₁)C(═O)R₂₃, —N(R₂₁)C(═O)OR₂₂, —N(R₂₁)C(═O)N(R₂₁)(R₂₂), substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted cycloalkyl; R₂₁ and R₂₂ are each independently H, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl; R₂₃ is each independently substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted C₃-C₈cycloalkyl; n is 0-4; p is 0-2; R₆ is H, or L-J-W; R₇ and R₈ are independently H or L-J-W; or R₇ and R₈ taken together form a bond; L and J are each independently a bond, substituted or unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, substituted or unsubstituted C₃-C₁₂ heteroarylene, —CO—, —O—, or —S—; W is H, or NR₂₅R₂₆; R₂₅ and R₂₆ are each independently H, substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, wherein L_(a) is —O—, or —OCH₂—.
 3. The compound of claim 2, wherein Ar is phenyl.
 4. The compound of claim 3, wherein R₃ is


5. The compound of claim 4, wherein Z is C(═O), NHC(═O), N(CH₃)C(═O), or S(═O)₂.
 6. (canceled)
 7. (canceled)
 8. (canceled)
 9. (canceled)
 10. The compound of claim 5, wherein R₆ and R₈ are H; and R₇ is L-J-W.
 11. The compound of claim 10, wherein L is a bond, substituted or unsubstituted C₁-C₆ alkylene, or substituted or unsubstituted C₃-C₆ cycloalkylene; and J is a bond, substituted or unsubstituted C₁-C₆ alkylene, substituted or unsubstituted C₃-C₆ cycloalkylene, substituted or unsubstituted C₁-C₆ heteroalkylene, substituted or unsubstituted C₂-C₇ heterocycloalkylene, substituted or unsubstituted C₆-C₁₂ arylene, or substituted or unsubstituted C₃-C₁₂ heteroarylene.
 12. The compound of claim 11, wherein L is a bond; J is —CH₂—; and W is NR₂₅R₂₆.
 13. The compound of claim 12, wherein R₂₅ is H, substituted or unsubstituted C₁-C₆ alkyl, or substituted or unsubstituted C₃-C₆ cycloalkyl; and R₂₆ is substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₃-C₆ cycloalkyl, substituted or unsubstituted C₁-C₆ heteroalkyl, substituted or unsubstituted C₂-C₇ heterocycloalkyl, substituted or unsubstituted C₆-C₁₂ aryl, or substituted or unsubstituted C₃-C₁₂ heteroaryl. 14-38. (canceled)
 39. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 40. (canceled)
 41. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient.
 42. The compound of claim 13, wherein R₂₅ is —CH₃ and R₂₆ is cyclopropyl or cyclobutyl.
 43. The compound of claim 42, wherein Y is phenyl.
 44. The compound of claim 43, wherein Z is C(═O).
 45. A compound having the structure: 